The Viruses and Other Infectious Agents

NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning, LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC 9781284240535_CH06_137_168.indd 137

© Eye of Science/Science Source. 6-4 6-2 False-color transmissionelectron microscopy showing twoherpessimplexviruses. 6-8 6-7 6-6 6-5 6-3 6-1 CHAPTER KEYCONCEPTS Infectious Agents The VirusesandOther NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC cause diseaseinanimalsandhumans. ciated withtumors andcancer. Thechapter concludes bydiscussing anotheruniqueinfectious agentthatalsocan structure, how they are classified, how they multiply, how they are cultured andidentified,how someare asso- causing disease.Inthischapter, we willstudy theviruses(highlightingCOVID-19 virus),focusing ontheirunique AIDS andnow coronavirus disease 19(COVID-19). Yet, aswe just read, virusescan be more thaninfectious agents tumors were inremission. Afew monthslater, thedoctors saidthetumors were gone.Amazing! the virusessothey could notcause cold sores. Over theweeks, asthetreatments continued thedoctors told her the of thousandsherpessimplex viruses,specifically theonesthatcause cold sores. Theresearchers hadmodified However, heroncologist suggested she tryanexperimental therapy usingviruses to treat suchmelanomas. Each time she had the tumor cut out. Thelatest biopsy of a stage IVmelanomawas devastating, andshewas scared. and Sophia had the melanomas removed. It was not long before she soon found another spot, and more after that. means the cancer cells have spread to nearby lymph nodes, but not yet to distant organs. Surgery was scheduled Could hermoles beskincancers? Shemadeanappointmentwithadermatologist to have thespots examined. nomas. Thearticle describedmelanomas as abnormal skin growths with irregular shape and uneven dark shading. skin moles, Sophiadidnotpay muchattention to themuntilsheread ahealth story aboutskincancers andmela - spread beyond theskinto distant organs, andshewas told shemighthave only 6monthsto live. Sophia gotthedevastating news. Thetumor biopsy was diagnosedasastage IVmelanoma.Theskincancer had Viruses to theRescue!

CHAPTER 6 Prions Are Noncellular Infectious Agent Emerging VirusesArisefrom GeneticRec Some VirusesAre Associated withHumanT Viruses andTheirInfections CanBeDetected inV Virus Replication Foll Viruses CanBeClassified byTheirGenome Viruses Have aSimple Structural Or Filterable Infectious Agents CauseDisease People usually thinkofvirusesasonethegreatest dangers to humans.After all,just look atviral diseaseslike A few weeks later, Sophiawas havinganexperimental therapy onhertumors. Thetherapy involved theinjection From the biopsy results, thedermatologist made adiagnosisofstage IIImelanoma.Astage IIImelanoma It allstarted whenthe35-year-old woman found two smallbrown growths onhercalf. Thinkingthey were just © Jones&Bartlett Learning LLC,anAscendCompany. NOTFORSALEORDISTRIBUTION. NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC ows aSetofCommonSteps ganization s ombination andMutation umors andCancers NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning, LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC arious Ways NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC NOT FORSALEORDISTRIBUTION © Jones&BartlettLearning,LLC 137 30/12/20 4:54 PM 138 Chapter 6 The Viruses and Other Infectious Agents

The development of the germ theory of disease in the This discovery is considered to be the beginning of 1880s helped scientists© recognize Jones disease& Bartlett patterns Learning, as- field LLC of virology, the scientific© study Jones of viruses & Bartlett. Learning, LLC sociated with a specificNOT bacterial FOR species.SALE ORHowever, DISTRIBUTION In 1898, foot-and-mouthNOT disease FOR (a SALEcontagious OR DISTRIBUTION some diseases, such as smallpox, measles, and rabies, disease among cattle, sheep, and deer) also was sus- resisted identification. They couldn’t be grown in a pected as being caused by a filterable virus, implying cell culture. It turns out that most of these diseases that there were viruses capable of infecting animals as were caused by viruses. well as plants. Three years later, American physician © Jones & Bartlett Learning, LLC Walter Reed and© Jones his group & inBartlett Cuba provided Learning, evidence LLC Viruses—ThenNOT FOR SALE and OR Now DISTRIBUTION linking yellowNOT fever FOR with aSALE virus, thusOR linkingDISTRIBUTION viruses In the late 1800s, tobacco growers in Europe noticed with human diseases. their tobacco plants were developing a mottled or mo- In 1915, English bacteriologist Frederick Twort saic pattern on the leaves, which came to be called discovered viruses that infected bacterial cells and two © Jonestobacco & Bartlett mosaic Learning, disease (TMD) LLC (Figure 6-1A). Two © Jonesyears later & Bartlettsuch viruses Learning, were identified LLC by French- NOT FORscientists, SALE Dimitri OR DISTRIBUTION Ivanowsky, a Russian botanist, and NOTCanadian FOR SALEscientist OR Felix DISTRIBUTION d’Herrelle. He called them Martinus Beijerinck, a Dutch botanist and microbiolo- bacteriophages (phage = “eat”), or simply phages, gist, independently filtered the crushed leaves of TMD- for their ability to destroy the bacterial cells they infected plants, hoping to trap what they believed were infected. bacterial cells on the filter, as the bacterial cells would In the 1930s, studies suggested that the tobacco © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC be too large to pass through. Rather, to their surprise, mosaic virus (TMV) was composed exclusively of the clear liquid passingNOT through FOR the SALE filter ORcontained DISTRIBUTION nucleic acid and protein, andNOT lacked FOR the SALE cellular OR DISTRIBUTION the infectious agent. When the liquid was placed on structure typical of prokaryotic and eukaryotic cells healthy leaves, TMD soon appeared. Throughout his (Figure 6.1B). Soon, advances in staining of viruses for studies, Beijerinck often referred to the infectious transmission electron microscopy verified that viruses agent in© theJones fluid & asBartlett the “virus” Learning, (virus = “poison”).LLC were not cellular.© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Figure 6-1 Tobacco mosaic disease and its virus Tobacco mosaic disease (A) is the result of a viral infection (B). A: Courtesy of Clemson University - USDA Cooperative Extension Slide Series, Bugwood.org; B: © Dennis Kunkel Microscopy/Science Source.

A B © Jones &An Bartlett infected tobacco Learning, leaf exhibiting LLC the mottled or mosiac © JonesFalse-color & Bartlett transmission Learning, electron microscopy LLC of the tobacco NOT FOR SALEappearance OR caused DISTRIBUTION by the disease. NOT FORmosiac virusSALE showing OR the DISTRIBUTION cylindrical (helical) rod-shaped structure of the virus particles. (Bar = 80 nm)

9781284240535_CH06_137_168.indd 138 30/12/20 4:54 PM KEY CONCEPT 6-2 Viruses Have a Simple Structural Organization 139

Today, scientists and microbiologists are con- diversity on Earth. The virosphere is massive, it is © Jones & Bartlett Learning, LLC © Jones & Bartletttinuing to Learning, find viruses LLC almost everywhere they look. incredibly diverse, and it has tremendous impact be- NOT FOR SALE OR DISTRIBUTION 31NOT FOR SALE OR DISTRIBUTION In fact, this so-called virosphere exceeds 10 vi- yond infection and disease. ruses and is the planet’s most abundant “life form.” Although some viruses are major causes of illness and disease, such as sudden acute respiratory Concept Check 6-1 syndrome coronavirus 2© Jones (SARS-CoV-2 & Bartlett )Learning, that caused LLC © Jones & Bartlett Learning, LLC the NOT FOR SALE ( OR DISTRIBUTION) pan- 1. Describe the major NOTevents FORleading SALE to the OR DISTRIBUTION coronavirus disease 2019 COVID-19 recognition of viruses as agents of infectious demic, many others drive global biogeochemical cy- disease. cles and are a collection of the largest store of genetic

© Jones & BartlettToday, approximately Learning, LLC200,000 different viruses have© Jones & Bartlett Learning, LLC NOT FOR SALEbeen ORidentified, DISTRIBUTION and presumably all organisms inNOT the FORViruses SALE OR Usually DISTRIBUTION Are Tiny tree of life are susceptible to infection by some type Infectious Agents of virus. Less than 7,000 viruses have been named Most viruses usually are tiny, ranging in size from and about 250, including SARS-CoV-2, have the about 30 nm to 200 nm, so they can be seen only with ability to infect ©human Jones cells. & BartlettSo, what Learning,exactly are LLCthe electron microscope© ( FigureJones 6-2 &). BartlettA few, however, Learning, LLC viruses? NOT FOR SALE OR DISTRIBUTIONare extremely large. TheseNOT giant FOR viruses, SALE such OR as DISTRIBUTION the

Figure 6-2 Size relationships among cells and viruses The© Jones sizes (not & drawn Bartlett to scale) Learning, of various LLCviruses relative to a eukaryotic© cell, Jones a cell &nucleus, Bartlett and Learning,the bacterium LLC Escherichia coli. Why are viruses so small? NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Rabies: 150 nm

Smallpox: 250© nmJones & Bartlett Learning,Polio: 28 nmLLC © Jones & Bartlett Learning, LLC NOT FOR SALEInfluenza: OR 100 nmDISTRIBUTION NOT FOR SALE OR DISTRIBUTION Eukaryotic cell 10,000 nm Tobacco mosaic: 240 nm SARS-CoV-2: 125 nm

Common cold: 70 nm © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Bacteriophage: 95 nm

9781284240535_CH06_137_168.indd 139 30/12/20 4:54 PM 140 Chapter 6 The Viruses and Other Infectious Agents

recently discovered mimivirus and pandoravirus, are molecule that consists of relatively few genes, ranging © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC the size of small bacterial cells. from less than 10 to a few hundred. NOT FOR SALE OR DISTRIBUTION NOT FOR SALENonetheless, OR DISTRIBUTIONall viruses are obligate, intracellular Together, the capsid with its enclosed genome parasites—that is, they depend on a host cell, the cell is called a nucleocapsid, and a complete infectious they infect, to multiply. This is because although viruses particle represents a virion. have the information to make more viruses, they lack the chemical machinery ©for Jones virus replication. & Bartlett Therefore, Learning, Enveloped LLC Viruses © Jones & Bartlett Learning, LLC when viruses break intoNOT living FORcells, theySALE take OR over DISTRIBUTION the The nucleocapsids of other viruses,NOT suchFOR as SALE the SARS- OR DISTRIBUTION cell genetic machinery of the cell, and use their own CoV-2, are surrounded by a flexible, loose-fitting viral-encoded instructions to make more viruses. membrane known as an envelope; such viruses, One simple way of separating the viruses is by therefore, are called enveloped viruses (Figure 6-3B). their structural© Jones differences. & Bartlett Learning, LLC The envelope© is Jonescomposed & ofBartlett lipids and Learning, protein, sim LLC- ilar to the host membranes. An enveloped virus can NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Nonenveloped Viruses lose its infectivity if the envelope is destroyed. In fact, these viruses are more susceptible to drying and disin- The simplest animal viruses, such as the polioviruses, fectants than are the nonenveloped viruses. consist of just two components: an indispensable nu- An enveloped virus often contains a layer or two of cleic acid core and a surrounding protein shell. Such vi- © Jones & Bartlett Learning, LLC © Jonesprotein, &called Bartlett the Learning, (or tegument), LLC sandwiched ruses represent ( ). matrix NOT FOR SALE ORnonenveloped DISTRIBUTION viruses Figure 6-3A NOTbetween FOR theSALE capsid OR and DISTRIBUTION envelope. The matrix helps The protein shell, called the , surrounds the capsid hold the nucleocapsid to the envelope. In some envel- viral genome while providing shape or symmetry to oped viruses, like the influenza viruses, the genome the particle. The capsid is built from individual protein exists as separate, nonidentical nucleic acid segments. subunits called that self-assemble into the capsomeres Many enveloped viruses also contain protein virus’s shape. On the virus© eitherJones special & Bartlett capsid proteins Learning, LLC © Jones & Bartlett Learning, LLC spikes that project from the envelope. These proteins called or other proteinNOT FORfibers SALEprotrude OR from DISTRIBUTION the NOT FOR SALE OR DISTRIBUTION spikes are capable of binding to host cell receptors and facil- surface. These external proteins help attach the virus to itating host cell entry. protein receptors on, and facilitate entry into, host cells. The capsid also protects the viral nucleic acid against Viruses Have Diverse Shapes chemical© andJones physical & Bartlett agents and Learning, other environmental LLC © Jones & Bartlett Learning, LLC fluctuations (e.g., temperature and pH changes). The self-assembly of the capsid generates the three- NOT FOR SALE OR DISTRIBUTION dimensional NOTshape, FOR or symmetry, SALE OR of the DISTRIBUTION virion. For The nucleic acid core, called the viral genome, contains one or more molecules of DNA or RNA that many, including those infecting humans, three sym- have the instructions to make more viruses. The ge- metries are possible. nome can be a double-stranded or a single-stranded • Helical Symmetry. Some capsids, such as those © Jonesform, & Bartlett depending Learning, on the specific LLC virus type. Usually © Jonesof the & rabiesBartlett virus Learning, and COVID-19 LLC viruses, exist in NOT FORthe SALEtightly packedOR DISTRIBUTION nucleic acid is a linear or circular NOT FORthe form SALE of a spiralOR DISTRIBUTION rod or filament and are said to

Figure 6-3 The structure of viruses Viruses are structurally simple, with some lacking an envelope (A) while others have an envelope (B).

A B Nonenveloped viruses have© aJones protein capsid & Bartlett made of Learning,Enveloped LLC viruses have a membrane-like© covering Jones that surrounds& Bartlett the Learning, LLC capsomer units that surroundsNOT and FOR protects SALE the genome. OR DISTRIBUTIONnucleocapsid. NOT FOR SALE OR DISTRIBUTION

Protein fiber (spikes) (receptor-binding protein) Spikes © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC RNA genome NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTIONNucleocapsid Capsid proteins

Envelope Capsid Nucleocapsid Envelope © Jones & BartlettCapsomers Learning,Genome LLC © Jones & Bartlett Learning,protein LLC

NOT FOR SALE ORPoliovirus DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

SARS-CoV-2

9781284240535_CH06_137_168.indd 140 30/12/20 4:54 PM KEY CONCEPT 6-2 Viruses Have a Simple Structural Organization 141 have ( ). The helix helical symmetry Figure 6-4A © JonesFigure & Bartlett 6-4 Viral Learning, symmetry LLC © Jones & Bartlettis a tightly Learning, wound LLC coil resembling a corkscrew or Viruses exhibit variations in shape, being helical (A), NOT FOR SALEspring. OR DISTRIBUTION NOT FORicosahedral SALE (ORB), or DISTRIBUTION complex (C). Although bacteriophages • Icosahedral Symmetry. Other viruses, such as the symmetrically are said to be complex, what herpesviruses (enveloped) and the polioviruses two symmetries do these viruses exhibit? (nonenveloped), have capsids in the shape of a A Helical Symmetry polyhedron with© Jones 20 triangular & Bartlett sides, Learning, and hence LLC The capsid forms a hollow,© Jones helical rod & inside Bartlett of which Learning, is LLC the virus genome. icosahedral NOT(icos FOR= “twenty”; SALE edrosOR DISTRIBUTION= “side”) NOT FOR SALE OR DISTRIBUTION symmetry (Figure 6-4B). Complex Symmetry. Some viruses have capsids • Envelope with a complex symmetry, meaning they have © Jonesseveral parts& Bartlett with different Learning, shapes LLC (Figure 6-4C). © Jones & Bartlett Learning, LLC Some bacteriophages, for example, have an icosa- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION hedral head with a collar and tail assembly in the Capsid shape of a helix. The smallpox virus, by contrast, is brick shaped, with protein filaments occurring in a swirling pattern at the surface. © Jones & Bartlett Learning, LLC © Jones & BartlettSARS-CoV-2 Learning, LLC Rabies virus NOT FOR SALEViruses OR DISTRIBUTION Have a Host Range NOT FOR SALE OR DISTRIBUTION B Icosahedral Symmetry and Tissue Specificity The capsid forms a 20-sided structure inside of which As a group, viruses can infect almost any cellular is the virus genome. organism in the domains Bacteria, Archaea, and Eu- karya. However, they© Jones must be & transmitted Bartlett Learning, to the right LLC © Jones & Bartlett Learning, LLC organism (host), andNOT then FOR often SALE infect aOR specific DISTRIBUTION cell or EnvelopeNOT FOR SALE OR DISTRIBUTION tissue in that host. Capsid

Virus Transmission © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC For a virus to spread and cause more infections, it NOT FOR SALE OR DISTRIBUTION NOT FOR SALEHerpes OR DISTRIBUTION simplex must be transmitted in some way from an infected in- virus dividual or a reservoir. A reservoir is the specific envi- Poliovirus ronment in which the virus naturally survives. Viruses can be transmitted to humans by direct contact © Jones & Bartletttransmission Learning, (Figure LLC 6-5). This includes such modes© Jones C& BartlettComplex Symmetry Learning, LLC as kissing, getting bit by an infected insect, or hav- The capsid forms a complex structure inside of which NOT FOR SALE OR DISTRIBUTION NOT FOR SALEis the virus OR genome. DISTRIBUTION ing sexual intercourse with an infected person. Vi- ruses also can be spread through indirect contact transmission. This involves such modes as ingesting contaminated food or water or contacting a contaminated , which© Jones is a nonliving& Bartlett object Learning, such as LLC © Jones & Bartlett Learning, LLC fomite Envelope a doorknob or cellNOT phone FOR that SALE harbors OR the DISTRIBUTION virus. Vi- NOT FOR SALE OR DISTRIBUTION ruses also can be carried airborne in small particles (aerosols and droplets) carried in the air. Sneezing or coughing can produce such respiratory particles. Smallpox virus © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning,Smallpox virus LLC Bacteriophage HostNOT FORRange SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION The host range refers to what organisms (hosts) the virus can infect. For example, the poliovirus only in- At the other extreme, a few viruses, such as the ra- fects humans. A person infected with the poliovirus bies virus, have a broad host range. These viruses infect © Jones & Bartlettspreads theLearning, virus from LLC feces into a water supply or,© by Jones humans & Bartlett and most Learning, warm-blooded LLC animals (e.g., bats, NOT FOR SALEtouch, OR into DISTRIBUTION food. Actually, polio is so contagious thatNOT FORskunks, SALE and ORdogs). DISTRIBUTION Direct contact with a rabies-infected direct contact with a person infected with the virus animal can transmit the virus into the bloodstream of can lead to infection in the recipient. the host through a bite from the rabid animal.

9781284240535_CH06_137_168.indd 141 30/12/20 4:55 PM 142 Chapter 6 The Viruses and Other Infectious Agents

How we know that susceptible host cells have Cell/Tissue Specificity © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC receptors to which virus surface proteins bind is ex- Even within its host range, many animal viruses only NOT FOR SALE OR DISTRIBUTION NOTplored FOR in SALE OR DISTRIBUTION . infect certain cell types or tissues within the host. This Investigating the Microbial World 6 lists some human viruses and their cell/ limitation is called . For exam- Table 6-1 cell/tissue specificity tissue specificity. ple, the host range for the human immunodeficiency virus (HIV) is a human,© Jonesbut once & in Bartlett the host, Learning, HIV LLC © Jones & Bartlett Learning, LLC primarily infects specific groups of susceptible white NOT FOR SALE OR DISTRIBUTIONConcept Check 6-2 NOT FOR SALE OR DISTRIBUTION blood cells. This is because the envelope of HIV has 2. Identify the role of each structure found on (a) a protein spikes to specifically bind to receptor mole- nonenveloped and (b) an enveloped virus. cules on these cells. Therefore, if a potential host cell 3. What shapes can viruses have, and what lacks the appropriate receptor or the virus lacks the structure determines that shape? complementary© Jones surface & Bartlett protein, Learning, the virus usually LLC can- 4. How does© viral Jones structur & eBartlett determine Learning, cell/tissue LLC not infectNOT that FOR cell. SALE OR DISTRIBUTION specificity?NOT FOR SALE OR DISTRIBUTION

Figure 6-5 Virus modes of transmission A concept map summarizing virus transmission by direct or indirect contact, or by airborne particles. Notice that © JonesCOVID-19 & Bartlett can be Learning, transmitted LLCin several ways. © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION VirusNOT Transmission FOR SALE OR DISTRIBUTION

can occur by

Direct© contact Jones & Bartlett Learning, LLCIndirect contact © JonesAirborne & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FORparticles SALE OR DISTRIBUTION through which involves involving

Human-to- Animal-to- Sexual Food and Droplets and © Joneshuman & Bartletthuman Learning, LLC Fomites © JonesInsects & Bartlett Learning, LLC intercourse water aerosols NOTcontact FOR SALEcontact OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

which can harbor which can carry with viruses causing which can carry viruses causing viruses causing viruses causing

Herpes Rabies Hepatitis B Viral West Nile Influenza © Jones & Bartlett Learning, LLC AIDS © Jones & Bartlett Learning, LLC COVID-19 COVID-19 COVID-19 gastroenteritis virus disease COVID-19 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Investigating the Microbial World 6 Finding the Correct© Jones Address & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION OBSERVATION: The flu virus and SARS-CoV-2 can infect cells of the respiratory epithelium. These cells have on their cell surface sialic acid (SA)–linked glycoprotein receptors that are recognized by flu viruses or ACE2 protein receptors that are recognized by SARS-CoV-2. QUESTION: Because one cannot see cell surface receptors with a microscope, how can we determine if the flu viruses and SARS-CoV-2© Jones viruses& Bartlett use these Learning, molecules asLLC receptors for infection? © Jones & Bartlett Learning, LLC HYPOTHESIS:NOT FOR Viruses SALE cannot OR infect DISTRIBUTION cells if the correct membrane receptorNOT is absent FOR or SALEis blocked OR on DISTRIBUTIONthe host cell. If so, removing or blocking the receptor molecules on susceptible host cells will prevent virus infection. EXPERIMENTAL DESIGN: Epithelial cells are treated in one of two ways to remove or block the presumed surface receptors. EXPERIMENT 1: Epithelial cells of the nasal mucosa are treated with neuraminidase, an enzyme that specifically © Jones removes& Bartlett sialic Learning, acids. The cells LLC are then exposed to flu viruses.© Jones & Bartlett Learning, LLC NOT FOREXPERIMENT SALE OR 2: DISTRIBUTION Epithelial cells of the nasal mucosa are treatedNOT FOR with an SALE antibody OR that DISTRIBUTION binds to ACE2 molecules on the cell surface. The cells are then exposed to SARS-CoV-2.

9781284240535_CH06_137_168.indd 142 30/12/20 4:55 PM KEY CONCEPT 6-2 Viruses Have a Simple Structural Organization 143

Sialic acid

Influenza © Jones & Bartlett Learning, LLC virus © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONInfluenza attaches to NOT FORNo attachment SALE ofOR DISTRIBUTION and infects host cell virus to host cell Experiment 2

Host cell Treat cells with antibody (binds to ACE2) Nucleus

SARS-CoV-2 attaches to No attachment of and infects host cell virus to host cell

©QUESTIONS Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT1. Is FORthe hypothesis SALE supported?OR DISTRIBUTION Answer by analyzing the results fromNOT each ofFOR the two SALE experiments. OR DISTRIBUTION 2. Explain the relationship between cell/tissue specificity and host cell receptors. 3. What would be the controls in each of these two experiments? You can find answers online in Appendix E.

Table 6-1 Examples of Viral Cell/Tissue Specificity Virus Cell/Tissue Specificity in Human Body Hepatitis A, B, C © Jones & Bartlett Learning, LLCLiver cells (hepatocytes) © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION HIV CD4 T lymphocytes, macrophages Human herpes simplex 1 and 2 Mucoepithelium Human papilloma Differentiating keratinocytes © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Influenza A Respiratory epithelium NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Norovirus Intestinal epithelium Poliovirus Intestinal epithelium, motor neurons Rabies Motor neurons © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALERhinovirus OR DISTRIBUTION NOT FORNasal SALEepithelium OR DISTRIBUTION SARS-CoV-2 Epithelium in many organs and tissues

9781284240535_CH06_137_168.indd 143 30/12/20 4:55 PM 144 Chapter 6 The Viruses and Other Infectious Agents

In the past, viruses have been classified by morphol- for cold sores (fever blisters) and chickenpox and ogy (nonenveloped and© enveloped), Jones & size,Bartlett capsid Learning, sym- LLCthe Poxviridae that includes© Jonesthe smallpox & Bartlett virus. Learning, LLC metry, the cells or tissuesNOT they FOR infect, SALE or the OR diseases DISTRIBUTION It is important to realize thatNOT all FOR these SALEviruses areOR DISTRIBUTION they cause. A more encompassing classification sys- catalogued by their genome type. For example, all tem based on evolutionary relationships is being de- the class I viruses are grouped together because they vised by the International Committee on Taxonomy have dsDNA. Each causes a vastly different disease. of Viruses (ICTV). At this writing, higher-order taxa In other words, if a person contracted mononucle- (phyla ©and Jones classes) & have Bartlett not been Learning, completely LLC devel- © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION osis, that infectionNOT willFOR not SALE cause ORchickenpox DISTRIBUTION in the oped. To date, six orders are recognized that comprise affected individual. Both viruses might be in the same 87 families, each ending with -viridae (e.g., Corona- dsDNA family (Herpesviridae), but they are quite dif- viridae). However, many other viruses have not yet ferent infectious disease agents. been assigned to a family. Viruses have been catego- The class II DNA viruses include the nonenvel- © Jonesrized & Bartlett into hundreds Learning, of genera; LLC each genus name ends © Jonesoped ssDNA & Bartlett viruses. Learning, The Parvoviridae LLC include one NOT FORwith SALE the suffix OR DISTRIBUTION-virus (e.g., human coronavirus). In NOTvirus FOR that SALEcauses a OR childhood DISTRIBUTION rash called fifth disease. this text, the family name (e.g., Coronaviridae) is used The class VII DNA viruses includes the Hepadna- when referring to the whole family of viruses and the viridae that cause hepatitis B. These viruses are dsDNA common name (e.g., SARS-CoV-2) when discussing a reverse transcribing viruses that must copy the DNA specific virus in a family. © Jones & Bartlett Learning,into LLC RNA, which, using a reverse© Jones transcriptase & Bartlett en- Learning, LLC NOT FOR SALE OR DISTRIBUTIONzyme, then is reverse transcribedNOT (RNA FOR to SALE DNA) ORfor DISTRIBUTION new viruses being replicated. Unlike class I, they can- Virus Classification Can Be not directly replicate their DNA into more DNA. Organized Based on Nucleic Acid© Type Jones & Bartlett Learning, LLC RNA Viruses© Jones & Bartlett Learning, LLC A popularNOT classification FOR SALE system OR ofDISTRIBUTION widespread use was A few virusesNOT have FORdsRNA SALE genomes OR (classDISTRIBUTION III). The developed by David Baltimore, an American biologist nonenveloped Reoviridae include the rotaviruses that and Nobel laureate. This system groups viruses into cause severe diarrhea in infected infants and young families based on the type of genome: DNA or RNA, children worldwide. single stranded (ss) or double stranded (ds), and en- The vast majority of RNA viruses have a ssRNA © Jonesveloped & Bartlett or nonenveloped. Learning, SEEING LLC THE CONCEPT © Jonesgenome &(classes Bartlett IV-VI). Learning, For these viruses,LLC the genome NOT FOR(Figure SALE 6-6) OR presents DISTRIBUTION this classification system. Please NOTis classifiedFOR SALE according OR DISTRIBUTION to the functionality of their refer to this figure as we describe the DNA viruses and RNA. These include: the RNA viruses. • Positive-Sense (+Sense) RNA Viruses (Class IV). On infection of a host cell, the ssRNA in the DNA Viruses © Jones & Bartlett Learning, LLC+sense RNA viruses can be© translatedJones & directly Bartlett by Learning, LLC Many viruses contain eitherNOT double-strandedFOR SALE OR (ds) DISTRIBUTION or the host cell ribosomes (thus,NOT + sense).FOR SALEIn fact, theOR DISTRIBUTION single-stranded (ss) DNA genomes with nucleocap- +sense RNA viruses are the largest group of RNA sids that are nonenveloped or enveloped. The class I viruses. Figure 6-6 identifies many of the families viruses include: and common diseases associated with that family. © Jones & Bartlett Learning, LLC Notice that© JonesCOVID-19 & Bartlettis in this group. Learning, LLC • NonenvelopedNOT FOR SALEdsDNA OR Viruses. DISTRIBUTION Two common • Negative-SenseNOT FOR (−Sense) SALE RNA OR Viruses DISTRIBUTION (Class nonenveloped dsDNA virus families are the Ad- V). On infection of a host cell, the ssRNA in the enoviridae, which includes viruses causing com- −sense RNA viruses must be converted into a mon colds, and the Papillomaviridae, which “readable” form; it cannot be translated directly by includes members causing common skin warts. the host cell ribosomes (thus, −sense). Therefore, © Jones• & EnvelopedBartlett Learning, dsDNA Viruses. LLC Several families © Jonesthe −sense& Bartlett RNA must Learning, be converted LLC into a +sense NOT FOR SALEhave enveloped OR DISTRIBUTION dsDNA, including the Herpesvir- NOT FORRNA, SALEwhich is OR then DISTRIBUTION translated by host ribosomes. idae whose members include viruses responsible Figure 6-6 identifies many of the families and

9781284240535_CH06_137_168.indd 144 30/12/20 4:55 PM KEY CONCEPT 6-3 Viruses Can Be Classified by heirT Genome 145

© Jones & BartlettFigure 6-6 Learning, SEEING THE LLC CONCEPT © Jones & Bartlett Learning, LLC NOT FOR SALEA concept OR DISTRIBUTION map detailing the Baltimore classificationNOT system FOR for SALE DNA and OR RNA DISTRIBUTION viruses The virus families causing human diseases are separated into seven classes (I–VII). Some of the distinctive human diseases associated with each family are indicated.

DNA Viruses © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC can have a genome that is NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

dsDNA reverse- dsDNA ssDNA transcribing Class I Class II and is Class VII © Jones & Bartlett Learning, LLC © Jonesand is & Bartlett Learning,that replicates LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTIONthrough an RNA intermediate Nonenveloped Enveloped Nonenveloped

Hepadnaviridae includes the includes the includes the Hepatitis B Adenoviridae Poxviridae Parvoviridae Liver cancer © Jones & Bartlett Learning,Common cold LLC Smallpox © Jones & BartlettSevere diarrhea Learning, LLC NOT FOR SALE OR DISTRIBUTIONViral meningitis NOT FOR SALE OR DISTRIBUTION Herpesviridae Papillomaviridae Chickenpox Cervical cancer Cold sores Common warts Mononucleosis © Jones & BartlettShingles Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION RNA Viruses

can have a genome that is

Nonenveloped + sense – sense Enveloped Class IV Class V © Jones & Bartlett Learning,includes the LLC and is© Jones & Bartlett Learning,that reLLCplicates and is through a DNA NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTIONintermediate Reoviridae Retroviridae Gastroenteritis AIDS

Nonenveloped Enveloped Enveloped © Jonesincludes & Bartlett the Learning,includes LLC the includes the © Jones & Bartlett Learning, LLC Picornaviridae Togaviridae NOT FOR SALE OR DISTRIBUTION Filoviridae NOT FOR SALE OR DISTRIBUTION Common cold Rubella Ebola virus Hepatitis A Encephalitis Orthomyxoviridae Polio disease Influenza

Flaviviridae Bunyaviridae Caliciviridae © Jones & Bartlett Learning, LLC Yellow fever © JonesHantavirus & Bartlett Learning, LLC Gastroenteritis West Nile fever pulmonary Paramyxoviridae NOT FOR SALE OR DISTRIBUTIONHepatitis C NOT FOR SALE OR DISTRIBUTION syndrome Measles Zika virus Mumps infection Rhabdoviridae Coronaviridae Rabies © Jones & Bartlett Learning, LLC COVID-19© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 145 30/12/20 4:55 PM 146 Chapter 6 The Viruses and Other Infectious Agents

common diseases associated with each family. Importantly, most RNA virus genomes are more © Jones & Bartlett Learning, LLC © Jones &Notice Bartlett that Learning, the viruses LLCcausing influenza are in error (mutation) prone when copying their RNA ge- NOT FOR SALEthis group. OR DISTRIBUTION NOTnome. FOR This SALE is because OR DISTRIBUTIONthese viruses lack the efficient • Positive-Sense (+sense) Reverse Transcribing proofreading system possessed by the dsDNA viruses Viruses (Class VI). Among the +ssRNA viruses, (class I) that is used to correct replication errors. one class of viruses behave in an unusual way Therefore, mistakes are made more often, and an in- analogous to class ©VII. Jones Members & Bartlett of the Retrovi Learning,- correct LLC nucleotides are incorporated© Jones into &the Bartlett RNA ge- Learning, LLC ridae, such as the NOThuman FOR immunodeficiency SALE OR DISTRIBUTION vi- nome being synthesized. Thus,NOT the FORgenomes SALE in RNA OR DISTRIBUTION rus (HIV), is in this group. After infecting a host viruses, such as the influenza viruses, have a higher cell, the virus uses its own reverse transcriptase probability to “genetically drift” due to mutations. enzyme to produce dsDNA from its ssRNA ge- The result might be new, potentially more infectious nome© Jones through & aBartlett reverse transcriptionLearning, LLCprocess. epidemic strains.© Jones Interestingly, & Bartlett coronaviruses, Learning, like LLC Only after the new dsDNA has integrated into SARS-CoV-2, do have a proofreading system to cor- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION the host cell genome can the viral DNA genes be rect some replication mistakes. Its error rate is about transcribed into mRNA and translated. Such vi- half that of the flu viruses. ruses in the class are referred to as retroviruses (retro = “backwards”) because of the backwards © Jones & transcriptionBartlett Learning, (RNA to DNA). LLC © Jones & Bartlett Learning, LLC NOT FOR SALEAs with OR the DISTRIBUTIONdsDNA viruses, each RNA virus is NOTConcept FOR SALE Check OR 6-3 DISTRIBUTION unique in terms of the infectious disease it causes even 5. How do DNA viruses differ from RNA viruses? though they might all be grouped in the same family.

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION KEY CONCEPT 6-4 Virus Replication Follows a Set © Jones & Bartlett Learning,of Common LLC Steps© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION The process of virus replication is one of the most remarkable events in nature. In this five-step pro- The Replication of cess, a virus (1) encounters and attaches to the ap- Bacteriophages Can Follow propriate host cell, (2) enters the host cell that is One of Two Pathways © Jonesa &thousand Bartlett or Learning,more times LLCits size, and (3) hijacks © JonesThe bacteriophages & Bartlett exhibit Learning, two strategies LLC of infection: NOT FORthe SALEmetabolism OR DISTRIBUTIONof the cell to construct viral parts NOTa lytic FOR (virulent) SALE pathway OR DISTRIBUTION and a lysogenic (temperate) that are then (4) assembled into new virus particles pathway. (Figure 6-7). New virions then are (5) released from the cell, the host cell often being destroyed (lysed) The Lytic Pathway in the process. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC One of the best-studied processes of virus replication Replication has beenNOT studied FOR in SALE a wide ORrange DISTRIBUTION of NOT FOR SALE OR DISTRIBUTION viruses and their host cells. Before we examine the an- is that carried out by bacteriophages of the T-even imal (human) viruses, we will look at the ubiquitous group (T for “type”). Bacteriophages T2, T4, and T6 bacteriophages because much of what we know about are in this group. They are large, complex, dsDNA virions with a characteristic head and tail structure viruses comes from phage studies. MicroFocus 6-1 briefly© highlights Jones &the Bartlett bacteriophages. Learning, LLC (Figure 6-8A).© The Jones tail fibers, & Bartlett like the Learning,spikes on animal LLC NOT FOR SALE OR DISTRIBUTION viruses, functionNOT to FORattach SALEthe phage OR to DISTRIBUTIONa bacterial cell. The T-even phages are virulent viruses, meaning they lyse the host cell while carrying out a lytic pathway Concept Check 6-4A of replication. We will use phage T4 replication in E. coli as a © Jones 6.& BartlettList the five Learning, steps of virus LLC replication. © Jones & Bartlett Learning, LLC model for the lytic pathway. An overview of the NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 146 30/12/20 4:55 PM KEY CONCEPT 6-4 Virus Replication Follows a Set of Common Steps 147

Figure 6-7 The steps of virus replication © Jones & BartlettVirus replication Learning, is a five-step LLC process. Why can’t viruses© Jones complete & replication Bartlett outsideLearning, of a host LLC cell? NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 1. Attachment The virion binds to the host cell using surface proteins (tail fibers, spikes) that bind to specific protein receptors on the host cell surface. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 2. Entry Latency The viral nucleic acid and sometimes the whole In some viruses, the nucleocapsid gains access to the cell cytoplasm. nucleic acid can enter a The freed nucleic acid is transported to the site at latent state, delaying which it will be expressed and replicated. replication until later. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

3. Biosynthesis The viral nucleic acid is replicated and viral proteins, including capsid and tail fiber/spike proteins, are made. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

4. Assembly Capsid proteins and viral nucleic acid are assembled into nucleocapsids. If the virus is enveloped, the envelope might be acquired as the © Jonesnucleocapsid & Bartlett buds from Learning,a cytoplasmic membrane. LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

5. Release The complete virions are released from the infected cell by lysis or budding. If the virus is enveloped, the envelope might be acquired as the nucleocap- © Jones & Bartlettsid budsLearning, from the plasma LLC membrane. © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Bacteriophages are viruses that infect bacterial cells. These so-called phages that look like lunar lander spacecraft (see figure)© Jones are everywhere—in & Bartlett Learning,soil, oceans, hotLLC springs, Arctic ice, and human© Jones intestines. & Bartlett They are theLearning, LLC most diverse and numerous biological agents on the planet, outnumbering the bacteria 10:1. That said, scientists don’t have a completeNOT understandingFOR SALE of OR their DISTRIBUTION roles in Nature. They do have some ideasNOT of their FOR impact SALE and OR DISTRIBUTION potential uses. Here are just two examples: ■ In the environment. Phages cause 10 quadrillion (1016) successful bacterial infections per second in the world’s oceans. This means that phages destroy up to 40% of all oceanic bacterial cells every day. © JonesFollowing their & Bartlett deaths, Learning, those carbon-containing LLC bacteria sink ©down Jones into the & marineBartlett sediment, Learning, providing LLC nutrients to organisms that live on the seafloor. Anything that bacteria do as decomposers, from breaking NOTdown FOR the SALE carcasses OR of DISTRIBUTION dead animals to converting atmosphericNOT nitrogen FOR into SALE plant food, OR isDISTRIBUTION at the mercy of the phages that potentially can infect and kill them. In fact, phages can influence the ocean’s food supply by limiting phytoplankton populations (photosynthetic protists and cyanobacteria) that are essential in the food chain. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC (continues) NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 147 30/12/20 4:55 PM 148 Chapter 6 The Viruses and Other Infectious Agents

12 False-color transmission electron ■ In the human body. There are an estimated one trillion (10 ) microscopy of phages attached to and phages in the human digestive tract. Although these viruses infecting a bacterial ©cell. Jones (Bar = &100 Bartlett nm) Learning,do not infect LLC human cells, they still can have© Jones an enormous & Bartlett Learning, LLC effect on the microbiome in our gut. Scientists are wondering © Lee D. Simon/Science Source. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION whether this “sea of phages” might influence our physiology, perhaps even helping to regulate our immune systems. In humans, phages are more than four times as abundant in the mucus layers of the gut as they are in the surrounding gut © Jones & Bartlett Learning, LLC environment. By sticking© toJones mucus, & phages Bartlett encounter Learning, more LLC NOT FOR SALE OR DISTRIBUTIONof their bacterial prey, suggestingNOT FOR that SALE phages OR might DISTRIBUTION protect the underlying cells from being infected by potential bacterial pathogens. In addition, reports have been published proposing that the cells lining the gut can transport phages (30 billion per day!) © Jones & Bartlett Learning, LLC into the© bloodJones and & organs Bartlett of the Learning, body. If correct, LLC what they are doing there is completely unknown. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION As you can see, much remains to be studied and discovered. Once scientists better understand the role of phages in the human body, it may not be farfetched to look at phages as a tool to manipulate the bacterial microbiome and even control our own © Jones & Bartlett cells.Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Figure 6-8 Bacteriophage structure, attachment, and genome entry Phage attachment (A) and genome entry (B) happen very quickly. Is the phage in this figure infecting a gram-positive or gram-negative© Jones cell? & Explain. Bartlett Learning, LLC © Jones & Bartlett Learning, LLC

NOT FOR SALE OR DISTRIBUTION B NOT FOR SALE OR DISTRIBUTION A For attachment, the tail fibers recognize receptors Following attachment, the tail and core contact (not shown) on the bacterial envelope. the cell and the core is driven through the cell envelope, allowing the DNA to enter the cytoplasm. Head Bacterial cell © Jones & Bartlett Learning, LLC DNA© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Tail Hollow core © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Tail NOT FOR SALE OR DISTRIBUTIONfiber NOT FOR SALE OR DISTRIBUTION

Cytoplasm DNA © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 148 30/12/20 4:55 PM KEY CONCEPT 6-4 Virus Replication Follows a Set of Common Steps 149

five-step process is presented in SEEING THE CON- cell envelope, the DNA is ejected through the core © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC CEPT (Figure 6-9). The five steps are as follows: and into the bacterial cytoplasm (Figure 6-8B). NOT FOR SALE OR DISTRIBUTION NOT FOR SALEThe ejection OR DISTRIBUTIONprocess takes less than two seconds, 1. Attachment. The first step in the replication path- and neither tail contraction nor DNA ejection re- way of a virulent phage occurs when phage and quires energy. After ejection, the useless empty bacterial cells randomly collide. If proteins on the capsid remains outside the wall. phage’s tail fibers© Jones match & Bartlettwith a complementary Learning, LLC 3. Biosynthesis. Having© Jonesentered &the Bartlett cytoplasm, Learning, the LLC receptor site NOTon the FOR cell envelope SALE ORof the DISTRIBUTION bacterial phage DNA quicklyNOT takes FORcontrol SALE of the hostOR cell’DISTRIBUTIONs cell, attachment will occur. The actual attachment metabolic machinery to make hundreds of copies (adsorption) consists of a weak chemical union of itself. As phage genes code for the disruption between phage and receptor site. of the host chromosome, the phage DNA uses ©2. JonesEntry. Following& Bartlett attachment, Learning, the LLC phage DNA the© bacterial Jones nucleotides & Bartlett and Learning, enzymes to LLC synthe- crosses the cell envelope. The tail of the phage size multiple copies of its genome. The DNA also NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION releases lysozyme, an enzyme that dissolves a por- codes for capsid proteins using the bacterial cell’s tion of the bacterial cell wall. The tail sheath then ribosomes, amino acids, and enzymes for the bio- contracts, and, as the tail core drives through the synthesis process.

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Figure 6-9 SEEING THE CONCEPT Bacteriophage replication The pattern of replication in bacteriophages (tail fibers not shown) can involve a lytic or lysogenic pathway.

Chromosome © Jones & Bartlett Learning,Phage DNA LLC © Jones & Bartlett Learning, LLC 1 Phage attachesNOT to bacterial FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION (host) cell and ejects the DNA.

2 © JonesPhage DNA & Bartlettenters the Learning, LLC © Jones & Bartlett Learning, LLC NOTcell FOR and circularizes SALE inOR the DISTRIBUTION NOT FOR SALE OR DISTRIBUTION cytoplasm.

Virulent phage Temperate phage 3 Phage DNA replicates, and • Phage DNA integrates into phage proteins synthesized. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLCbacterial chromosome as a NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION prophage. Prophage 4 New phages assembled.

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT• Many FOR cell divisionsSALE mightOR DISTRIBUTION occur normally, copying the prophage into all progeny cells. 5 Cell lysis releases new phage particles. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE •OR Under DISTRIBUTION “stress” conditions, the phage detaches from the Lytic pathway chromosome, initiating a lytic pathway.

9781284240535_CH06_137_168.indd 149 30/12/20 4:55 PM 150 Chapter 6 The Viruses and Other Infectious Agents

4. Assembly. After the phage parts are made, they are produced with little delay between attachment © Jones & Bartlett Learning, LLC © Jones &self-assemble Bartlett Learning, into complete LLC virions. The enzymes and release. NOT FOR SALEencoded OR by DISTRIBUTIONphage genes guide the assembly in NOT FORImportantly, SALE notOR every DISTRIBUTION phage infection spells di- systematic fashion. In one area of the host cyto- saster for the bacterial cell. Bacterial cells can modify plasm, phage heads and tails are assembled from the receptors on their surface (through mutation) so protein subunits; in another area, the heads are the phages have no place to attach. Bacterial cells also packaged with DNA;© andJones in a &third Bartlett area, the Learning, tails have LLC a type of “immune defense,”© Jones called the& Bartlett CRISPR- Learning, LLC are attached to the heads.NOT FORAll this SALE assembly OR occurs DISTRIBUTION Cas system, which is capableNOT of recognizing FOR SALE and deOR- DISTRIBUTION without any input of metabolic energy by the bac- stroying foreign (viral) DNA that enters the cell. Of terial cell. course, viral mutations can occur so phages can get 5. Release. For some phages, lysozyme, encoded by past the bacterial “immune” defenses. In the end, it the© bacteriophage Jones & Bartlett genes late Learning, in the replicative LLC cy- often becomes© aJones molecular & Bartlettarms race Learning,between phage LLC cle, degrades the bacterial cell wall. Mature phage and bacterial cells as to whether the predator (phage) NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION particles now burst out from the ruptured bacte- or prey (bacterial cell) comes out on top. rial shell and are set free to infect more bacterial This ability of virulent phage to kill bacterial cells cells. has important medical significance, asMicroFocus 6-2 describes. © Jones & TheBartlett number Learning, of phages releasedLLC from an infected © Jones & Bartlett Learning, LLC NOT FORbacterial SALE cell OR is calledDISTRIBUTION the burst size. Although this NOT FOR SALE OR DISTRIBUTION size depends on the volume of the bacterial cell, burst The Lysogenic Pathway size typically ranges from 50 to a few hundred phages Other phages infect bacterial cells in a slightly per infected cell. Therefore, the lytic pathway rep- different way, called a lysogenic pathway (see resents a productive infection because many virions Figure 6-9). For example, lambda (λ) phage also © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

MicroFocus 6-2 Phage© Jones Therapy & Bartlett and Superbugs Learning, LLC © Jones & Bartlett Learning, LLC WhenNOT bacteriophages FOR SALE were ORidentified DISTRIBUTION in the early 1900s, IllustrationNOT of a phage FOR infection SALE of OR a superbug. DISTRIBUTION some scientists, including one of their discoverers, Felix (Bar = 300 nm) d’Herrelle, began to promote phages as therapy for curing © Nobeastsofierce/Shutterstock dreaded bacterial diseases such as cholera and bubonic plague. D’Herrelle and others assumed that if phages © Jones could& Bartlett destroy Learning,bacterial cells LLC in culture, why not try using © Jones & Bartlett Learning, LLC NOT FORthem SALE to destroy OR DISTRIBUTION bacterial cells causing diseases in the NOT FOR SALE OR DISTRIBUTION human body. Consequently, in 1919, they treated four children suffering from bacterial dysentery. All four began to recover within 24 hours. Phage therapy, however, never became widespread, partly due to the rise and availability of antibiotics in the 1940s© Jonesand 1950s. & Today,Bartlett as antibiotic Learning, LLC © Jones & Bartlett Learning, LLC resistance reaches a crisisNOT level FOR and SALEmore and OR more DISTRIBUTION NOT FOR SALE OR DISTRIBUTION superbugs are appearing, phage therapy is experiencing a slow rebirth. Here is a list of some studies on phage therapy in clinical medicine. ■ A ©Polish Jones microbiologist & Bartlett injected Learning, a solution LLC of phages into © Jones & Bartlett Learning, LLC 550NOT patients FOR with SALE a blood OR infection. DISTRIBUTION Each patient benefited NOT FOR SALE OR DISTRIBUTION from the treatment, and the researchers reported that several patients appeared to be completely cured. ■ Austrian researchers engineered bacteriophages to kill bacterial cells without lysing them. These phages were 10 times more lethal than the natural phages. ■ A Boston research team engineered a phage to attack and destroy bacterial biofilms, which often are the cause © Jones & Bartlettof human infectionsLearning, and LLCdisease and are often antibiotic© resistant.Jones & Bartlett Learning, LLC ■ A group of Italian researchers identified a phage capable of curing 97% of mice infected with a deadly form of NOT FOR SALEmethicillin-resistant OR DISTRIBUTION Staphylococcus aureus (MRSA). NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 150 30/12/20 4:55 PM KEY CONCEPT 6-4 Virus Replication Follows a Set of Common Steps 151

© Jones & Bartlett ■ The FDALearning, has approved LLC a clinical trial using phages© Jones with people & Bartlett having bacterial Learning, infections LLC due to venous leg NOT FOR SALE ulcers.OR DISTRIBUTION No harm to the volunteers was reportedNOT from the FOR treatment. SALE OR DISTRIBUTION ■ Several biotech companies are conducting clinical trials that use phage cocktails to treat Pseudomonas aeruginosa, MRSA, E. coli, and other infections caused by bacterial pathogens. ■ The European Phagoburn study is evaluating phages as treatment for infections resulting from burn wounds. At a time when bacterial resistance to antibiotics is increasing, phage therapy using “phage cocktails,” or phage enzymes, is on the© Jonesrebound. &Although Bartlett many Learning, of these phage LLC therapy studies are in early© clinicalJones trials, & Bartlett the use of Learning, LLC phage therapy holdsNOT great FOR potential SALE as OR a complementary DISTRIBUTION approach that, along with properNOT antibiotic FOR SALE use, might OR DISTRIBUTION provide optimal effects for patients with antibiotic resistant superbug infections (see figure). If you want to learn more about phage therapy, read The Perfect Predator (New York: Hachette Book Group. 2019) that in layperson’s terms recounts the global search by an infectious disease epidemiologist for phages to save her husband’s life as he suffered an overwhelming, life-threatening superbug infection. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION infects E. coli but might not immediately enter a lytic pathway after entry. Instead, after attaching and en- Concept Check 6-4B tering the bacterial cell, the phage dsDNA integrates What is virus latency? © Jones & Bartlettinto the bacterialLearning, chromosome LLC as a . Bac© Jones- 7.& Bartlett Learning, LLC prophage 8. Why would it be advantageous for a phage to NOT FOR SALEteriophages OR DISTRIBUTION participating in this cycle are knownNOT as FOR SALEcarry out OR a lysogenic DISTRIBUTION pathway rather than a lytic temperate (self-controlled) phages because they pathway? do not immediately kill the host bacterial cell. In a lysogenic pathway, the bacterial cell survives the infection and continues© Jones to grow & Bartlett and divide Learning, normally. LLCAnimal Virus Replication© Jones & Bartlett Often Learning, LLC Consequently, asNOT the bacterial FOR SALE cell goes OR through DISTRIBUTION cell NOT FOR SALE OR DISTRIBUTION division, the prophage is replicated because it is part Results in a Productive Infection of the bacterial chromosome. Following division, Like bacteriophages, animal viruses often have brief each daughter cell will have the prophage as part of but eventful “lives” as they infect cells and produce its bacterial genome. Because the prophage remains more virions. Such a productive infection retains the five common steps of virus replication described for “inactive,”© Jones the& Bartlett infection Learning,is referred LLCto as a latent © Jones & Bartlett Learning, LLC the bacteriophages. An overview of the replication infectionNOT FOR. SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION As cell divisions continue for an undefined process for a ssRNA (+sense) virus (class IV), such as period, all daughter cells are “infected” with the the SARS-CoV-2, is presented here (Figure 6-10): prophage. Usually at some point, the bacterial cells 1. Attachment. Animal viruses infect host cells by © Jones & Bartlettbecome stressedLearning, (e.g., LLC lack of nutrients, presence© of Jones &binding Bartlett to receptorsLearning, on the LLC host cell’s plasma mem- harmful chemicals in the environment). This triggers brane. This binding is facilitated by capsid spikes NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION the prophage to detach itself from the bacterial chro- spread over the surface of the envelope. Although mosome (see Figure 6-9) and initiate a lytic pathway, the virus does most of its replication in the upper lysing the bacterial cells as new λ phages are released. respiratory tract, other tissues in the lungs, digestive The CRISPR-Cas system mentioned earlier is system, urogenital system, nervous system, and cir- more than a defense© Jones against foreign& Bartlett DNA enteringLearning, the LLC culatory system of the© humanJones body & Bartlett contain recepLearning,- LLC cell. The CRISPR-CasNOT system FOR is SALE actually OR a surveillance DISTRIBUTION tors to which SARS-CoV-2NOT FORcan bind. SALE Consequently, OR DISTRIBUTION system; that is, the system can recognize whether this virus has quite a broad tissue specificity. any incoming foreign DNA is potentially destructive 2. Entry. Viral entry often involves the passage of or beneficial. For example, the bacterial pathogen the intact nucleocapsid into the cytoplasm. Once Corynebacterium© Jones & Bartlett diphtheriae Learning, is the infectious LLC agent in ©the Jones cytoplasm, & Bartlett the nucleocapsid Learning, disassembles LLC ofNOT diphtheria. FOR SALE The protein OR DISTRIBUTION toxin produced by these freeingNOT the FOR genome SALE in a processOR DISTRIBUTION called uncoating. cells is coded by a gene that the organism gained as For the Coronaviridae, the genome remains in the a result of a lysogenic infection; that is, the infecting cytoplasm where virus replication occurs. virus carried the toxin-coding gene. Because this gene 3. Biosynthesis. The virus DNA is replicated many is beneficial from the pathogen’s perspective, it is not times to produce new genomes that will be in- © Jones & Bartlettdestroyed Learning, by CRISPR-Cas. LLC We are only now begin© Jones- &corporated Bartlett Learning,into new viruses. LLC The viral genome NOT FOR SALEning toOR understand DISTRIBUTION this adaptive immune ability thatNOT FOR SALEalso supplies OR DISTRIBUTION (expresses) the genetic codes to syn- bacteria possess. thesize about 29 virus proteins, including capsid

9781284240535_CH06_137_168.indd 151 30/12/20 4:55 PM 152 Chapter 6 The Viruses and Other Infectious Agents

Figure 6-10 Replication of a single-stranded (class IV) RNA virus © JonesThe & replication Bartlett cycleLearning, for an RNA LLC virus, such as SARS-CoV-2,© involves Jones genome & Bartlett replication, Learning, biosynthesis LLC of virus NOT FORproteins, SALE and OR assembly DISTRIBUTION before each virus is released. Inset:NOT Summary FOR of classSALE IV replication.OR DISTRIBUTION EMS: endomembrane system. 1 Spike Attachment Virus enters body and spikes facilitate attachment to © Jones &Nucleocapsid Bartlett Learning, LLC re©ceptors Jones on host & plasmaBartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION emmbraneNOT FOR. SALE OR DISTRIBUTION

SARS-CoV-2 2 Entry 1 Plasma membrane • Fusion of virus envelope with plasma membrane © Jones & Bartlett Learning, LLC © Jones & Bartlett releases nucleocapsidLearning, LLC into host cell. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE• Nucleocapsid OR DISTRIBUTION uncoats. Virus 3 RNA 3 2 Biosynthesis

Translation Virus RNA is: +ssRNA Host cell RNA replication • Replicated in to hundreds cytoplasm © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, of copies. LLC • Translated into capsid Biosynthesis NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION proteins (in cytoplasm). EMS • Translated into spike and –ssRNA Proteins viral envelope proteins (in EMS). Capsid +ssRNA proteins 4 © Jones & CeBartlettll nucleus Learning, LLC Vesicles As©sembl Jonesy & Bartlett Learning, LLC Assembly • Spike and envelope NOT FOR SALE OR DISTRIBUTION NOT proteins FOR assembled SALE in OR DISTRIBUTION EMS - derived vesicles. 4 • A viral RNA associates with and is taken into a vesicle.

5 © Jones & Bartlett Learning, LLC © Jones & BartlettRelease Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE• Each OR vesicle DISTRIBUTION carries an assembled virus particle to the host plasma membrane, where the vesicle fuses with the membrane. • Membrane fusion releases © Jones & Bartlett Learning,5 LLC © Jones & Bartlett Learning, the virus LLC that can NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION infect additional cells.

proteins, viral envelope proteins, and spike pro- 5. Release. In the final stage, the vesicle membrane teins, using the host’s© Jones available & buildingBartlett blocks. Learning, LLCfuses with the plasma membrane,© Jones releasing& Bartlett the Learning, LLC Some of the proteins,NOT like FOR the viral SALE envelope OR proDISTRIBUTION- enclosed virion into the extracellularNOT FOR space.SALE This OR DISTRIBUTION teins and the spike proteins, are produced within process, called budding, need not always kill or the endomembrane system (EMS) and vesicles damage the cell during release. The number of viri- derived from the Golgi apparatus. ons released (burst size) from an infected host cell 4. Assembly.© Jones Once & Bartlettall the viral Learning, parts are made,LLC the again depends© Jones on the & volumeBartlett of Learning,the host cell. LLC In newNOT genomes FOR and SALE scattered OR DISTRIBUTIONproteins are brought general, theNOT burst FOR size SALEtypically OR ranges DISTRIBUTION from 500 to together for the construction of new viruses. The several thousand virions per infected host cell. assembly for enveloped viruses like the Corona- viridae requires the acquisition of an envelope. In this step, envelope proteins and spike proteins are © Jones & incorporatedBartlett Learning, into a cytoplasmic LLC membrane derived © JonesConcept & Bartlett Check Learning,6-4C LLC NOT FOR SALEfrom vesicles OR DISTRIBUTION originating in the Golgi apparatus. NOT FOR SALE OR DISTRIBUTION 9. Describe the five steps for the replication of a The ssRNA genome and attached capsid proteins class IV ssRNA (+sense) virus like SARS-CoV-2. (nucleocapsid) then merge with a vesicle.

9781284240535_CH06_137_168.indd 152 30/12/20 4:55 PM KEY CONCEPT 6-4 Virus Replication Follows a Set of Common Steps 153

the lips. Then, the virus enters a latent infection by in- © Jones & Bartlett Learning, LLC © Jones & BartlettSome Learning, Animal LLC Viruses Produce fecting a nearby sensory neuron. HSV undergoes latency NOT FOR SALEa Latent OR DISTRIBUTION Infection NOT FORas the SALE viral dsDNAOR DISTRIBUTION enters the neuron’s cell nucleus. No Most RNA viruses, including the Coronaviridae, only go virions are produced for months or years until some through a productive infection and produce hundreds of stress event reactivates the viral dsDNA. The virus then new virions that lyse the host cell on release. However, reinfects epithelial cells on the lip, and a new productive many of the DNA© viruses Jones (class I) & Bartlett and the Learning,Retroviridae LLCinfection (cold sores) can© occur. Jones & Bartlett Learning, LLC (class VI) can establishNOT a FORlatent SALE(or persistent) OR DISTRIBUTION infection. Retroviridae, suchNOT as HIV, FOR also SALE carry OR out DISTRIBUTION la- This “dormancy” is characterized by repression of most tent infections. However, in this group of viruses, viral gene expression. For example, some Herpesviridae, the virus carries the enzyme reverse transcriptase, such as the herpes simplex virus (HSV), can generate a which, as described earlier, is used to reverse tran- productive infection and cause cold sores to appear on © Jones & Bartlett Learning, LLC scribe ©its Jones+ssRNA & intoBartlett dsDNA Learning, (Figure 6- LLC11). The NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Figure 6-11 Formation of a provirus by HIV In Retroviridae such as HIV, the reverse-transcribed dsDNA enters the cell nucleus and integrates into a chromosome as a provirus. Inset: Summary of retrovirus replication. What advantage is gained by genome integration as a provirus? HIV © Jones & Bartlett Learning, LLCMatrix RNA© Jones & Bartlett Learning, LLC protein NOT FOR SALE OR DISTRIBUTION ReveNOTrse transcriptaseFOR SALE OR DISTRIBUTION +ssRNA Reverse 1 transcriptase Attachment and Entry dsDNA HIV typically infects T lymphocyte helper T lymphocytes.© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC • In the cytoplasm,NOT theFOR SALE OR DISTRIBUTIONViral RNA NOTInt FORegration SALE OR DISTRIBUTION nucleocapsid uncoats, DNA (single strand) releasing the viral RNA. 1 mRNA DNA (double helix) 2 Biosynthesis Reverse Transcription © Jonesand Integration& Bartlett Learning, LLC 2 © Jones & Bartlett Learning, LLC NOT FOR• The viral SALE revers eOR DISTRIBUTION NucleusNOT FOR SALE ORPr DISTRIBUTIONoteins transcriptase uses the viral RNA to synthesize Assembly a DNA strand and then Host cell uses the DNA strand to DNA complete the double © Jones & Bartlett Learning, helix. LLC © Jones & BartlettProvirus Learning, LLC • The viral DNA moves to NOT FOR SALE OR the DISTRIBUTION cell nucleus where NOT FOR SALE3 OR DISTRIBUTION Viral RNA 3 it integrates into the cell Viral RNA Biosynthesis DNA, forming a provirus. When activated, the • The provirus can provirus: remain inactive (latent • Is transcribed into infection).© Jones & Bartlett Learning, LLC © Jonesmultiple copies& Bartlett of new Learning, LLC NOT FOR SALE OR DISTRIBUTION NOTviral FOR RNA genomesSALE and,OR DISTRIBUTION Viral as mRNA, translated into proteins viral capsid proteins and spikes. 4 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

HIV 4 Assembly and Release Once the viral parts are made and the virus buds © Jones & Bartlett Learning, LLC from the© cell: Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION • Viral enzymesNOT FORconstruct SALE OR DISTRIBUTION the capsid and produce a functioning mature virus.

9781284240535_CH06_137_168.indd 153 30/12/20 4:55 PM 154 Chapter 6 The Viruses and Other Infectious Agents

dsDNA then enters the host cell nucleus. Similar to Scientists believe the ERVs are the result of ancient © Jones & Bartlett Learning, LLC © Jonesthe & temperate-Bartlett Learning,phage DNA LLCin bacteria, the dsDNA retroviral infections that integrated into the germline NOT FORbecomes SALE integrated OR DISTRIBUTION randomly into the DNA of one NOTmany FOR thousands SALE of OR years DISTRIBUTION ago. Although most of these chromosome. This integrated viral genome is re- sequences no longer function in virus replication, a ferred to as a provirus, and it represents a unique few have evolved into performing essential functions and stable association between the viral DNA and for human survival and development. The chapter on the host genome. However,© Jones at any & time,Bartlett the proviLearning,- Gene LLC Transfer, Genetic Engineering,© Jones and & GenomicsBartlett Learning, LLC rus can be reactivated andNOT a productiveFOR SALE infection OR DISTRIBUTION in- describes some of the proposedNOT roles FOR for ERVs. SALE OR DISTRIBUTION volving biosynthesis, assembly, and release of new virions will ensue. The advantage for the viral DNA to exist as a provirus is that every time the host cell Viral Infections in Humans Can Be Treated but Not Cured divides© the Jones provirus & willBartlett be replicated Learning, along LLC with the © Jones & Bartlett Learning, LLC host genome and be present in all progeny cells. With the possible exception of hepatitis C, no human NOT FOR SALE OR DISTRIBUTION viral disease NOTcan be FOR cured. SALE Antibiotics OR DISTRIBUTION do not work on viruses because, unlike bacteria, which attack the The Human Body Has a Resident body’s cells from the outside, viruses copy themselves Virome inside cells. Viruses can’t replicate on their own and © JonesResearchers & Bartlett have Learning, discovered LLC that many viruses nor- © Joneslack the &cellular Bartlett structures Learning, that antibioticsLLC typically NOT FORmally SALE can liveOR on DISTRIBUTION and in the human body without NOTtarget. FOR A numberSALE ORof antiviral DISTRIBUTION drugs have been devel- causing disease. This human virome can be found oped to ease the symptoms or shorten the duration on the skin and in the blood, lungs, and gut. What of a viral infection, and some viral diseases, such as these latent viruses are doing remains a mystery. Some smallpox, measles, and hepatitis B, can be prevented might be responsible for unsolved unexplained dis- with the use of vaccines. Figure 6-12 summarizes the eases that sometimes appear© Jones in individuals, & Bartlett especially Learning, outcomes LLC for animal virus infections.© Jones & Bartlett Learning, LLC those with a weakenedNOT immune FOR system. SALE Other OR DISTRIBUTIONresi- NOT FOR SALE OR DISTRIBUTION dent virus might be harmless or even be beneficial in some mysterious way. Besides these mysterious viruses, humans (and Concept Check 6-4D all vertebrates)© Jones have & Bartlett fragments Learning, of past viral LLC infec- © Jones & Bartlett Learning, LLC tions embeddedNOT FOR in SALEthe cellular OR DISTRIBUTIONDNA. In fact, about 10. DescribeNOT the process FOR SALE of provirus OR formation. DISTRIBUTION 8% of the human genome contains what are called 11. What is the human virome? 12. Why can’t antibiotics be used to treat and cure human endogenous retroviruses (ERVs), which viral infections and viral diseases? represent DNA sequences from the Retroviridae. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION KEY CONCEPT 6-5 Viruses and Their Infections Can Be Detected in Various Ways © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Viruses cannot be grownNOT independently FOR SALE in a cultureOR DISTRIBUTION as of a single layer (i.e., monolayerNOT) FORof cells SALE in a cul OR- DISTRIBUTION a solid mass the way bacteria or fungi form colonies ture dish. Then, a suspension of viruses is added. on agar because viruses need to get inside host cells to The viruses will lyse the host cells, and the released replicate. Therefore, phages must be inoculated onto virions then infect more cells. Eventually, enough a lawn© of Jones bacterial & cells Bartlett or animal Learning, viruses inoculated LLC cells will be ©lysed Jones that &the Bartlett observer Learning, can see a clear LLC into culturedNOT FORhuman SALE or animal OR cells. DISTRIBUTION For example, vi- zone with theNOT naked FOR eye. SALEThis clear OR zone DISTRIBUTION within the rologists can use human cells in culture to grow flu dense “lawn” of bacterial cells or stained monolayer viruses that are needed for a variety of research pur- of animal cells is called a plaque (Figure 6-13B). The poses (Figure 6-13A). assumption is that each plaque started from a single Virus numbers can be determined by carrying virus infecting one cell. Therefore, by counting the © Jonesout & aBartlett plaque assayLearning,. For phages, LLC bacterial cells are © Jonesnumber &of Bartlett plaques, Learning,one can estimate LLC the number NOT FORallowed SALE to ORgrow DISTRIBUTION and cover the surface of a culture NOTor concentrationFOR SALE ORof viruses DISTRIBUTION that were added to the dish. For animal viruses, animal cell cultures consist culture plate.

9781284240535_CH06_137_168.indd 154 30/12/20 4:55 PM KEY CONCEPT 6-5 Viruses and Their Infections Can Be Detected in Various Ways 155

Figure 6-12 Potential outcomes for animal virus infection of a host cell © Jones & BartlettAs depicted Learning, in this concept LLC map, depending on the virus© Jones and host & cell Bartlett interaction, Learning, the host cell LLC might be killed or NOT FOR SALEsurvive. OR Name DISTRIBUTION a virus associated with each of the threeNOT outcomes: FOR productive SALE OR infection, DISTRIBUTION cell death, latent infection.

Animal Virus

infects © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONHost cell NOT FOR SALE OR DISTRIBUTION

replication viral DNA causes association/provirus causes © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONProductive NOTLatent FOR SALE OR DISTRIBUTION infection infection

that permits with virion release causing © Jones & Bartlett Learning, LLC © Jones & BartlettSurvival Learning, of LLC host cell NOT FOR SALE OR DISTRIBUTION NOT FORviral SALE OR DISTRIBUTION reactivation Cell lysis Budding can result in

which results in © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Death of Survival of NOT FORhost cell SALE ORhost DISTRIBUTION cell NOT FOR SALE OR DISTRIBUTION

allows for

More viruses © Jones & Bartlett Learning, LLCto be shed © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Figure 6-13 Virus culture and virus estimation © Jones & BartlettViruses can Learning, be cultured LLC in susceptible animal cells in© culture Jones (A) &while Bartlett the number Learning, of viruses LLC present can be estimated NOT FOR SALEby a plaque OR DISTRIBUTION assay (B). About how many plaques are thereNOT on FORthe top SALE middle plate?OR DISTRIBUTION What does this tell you about the number of virus particles that were originally added to the cell culture? Courtesy of Robert Denty/CDC.

A A scientist uses a pipette to transfer a liquid suspension of flu B A CDC scientist examines the results of a plaque assay. Each viruses into each of the six well plates containing susceptible clear spot on the stained plate is a plaque, representing the host cells in cultur©e. Jones & Bartlett Learning, LLC result of a single virus particle© Jones infection. & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 155 30/12/20 4:55 PM 156 Chapter 6 The Viruses and Other Infectious Agents

microscopy can be used to detect the presence of cy- © JonesProcedures & Bartlett Learning, and Tools LLC Exist © Jones & Bartlett Learning, LLC toplasmic and nuclear inclusion bodies caused by NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION to Identify Viruses and Virus virus infection and replication (Figure 6-14A). Infections When viruses replicate in a cell culture, they of- The overall responsibility of a clinical microbiology ten cause a noticeable physical change in the infected laboratory (CML) is to help physicians in the diag- cells. This change, called the cytopathic effect nosis of infectious diseases.© Jones For bacterial & Bartlett infections, Learning, (CPE) LLC, often is detected in stained© Jones cells as µscopic Bartlett Learning, LLC clinical specimens oftenNOT can FORbe isolated SALE and OR grown DISTRIBUTION alterations to cell structure. ThisNOT includes FOR aSALE rounding, OR DISTRIBUTION in culture so tests can be performed to identify the swelling, or shrinkage of cells or the formation of mul- pathogen. Again, because viruses must infect host tinucleate giant cells called syncytia (Figure 6-14B). cells for replication, the virology section of the CML A SARS-CoV-2 infection in cultured cells causes a uses a variety© Jones of other & Bartlett procedures Learning, and tools to LLC assist in rounding up ©of Jonescells and & their Bartlett detachment Learning, from theLLC culture plate surface. the diagnosisNOT FORof viral SALE infections. OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION The diagnosis of some viral infections, such as Table 6-2 lists several of the cell inclusions and flus and colds, are usually straightforward based cytopathic effects associated with viral infections of on symptoms and might not require further labo- human cells. ratory confirmation unless the specific strain of the Some viral diseases can be diagnosed through im- © Jonesvirus & Bartlett needs to Learning,be determined. LLC Some viral infections © Jonesmunodiagnostic & Bartlett procedures. Learning, These LLC are described in NOT FORleave SALE their ORmark DISTRIBUTION on the infected individuals. Mea- NOTthe FORchapter SALE on Diagnosing OR DISTRIBUTION Infections. sles, for example, is accompanied by Koplik spots, which are a series of bright red patches with white pimple-like centers on the lateral mouth surfaces. Mumps and chickenpox© areJones associated, & Bartlett respectively, Learning, LLCConcept Check 6-5 © Jones & Bartlett Learning, LLC with swollen salivary glandsNOT FORand teardrop-like SALE OR DISTRIBUTIONskin NOT FOR SALE OR DISTRIBUTION lesions. 13. Describe the plaque assay and what it is Detection of the actual virus, however, is not al- used for. 14. Explain how some viruses can be identified ways so straightforward. The CML might use electron simply by observing an infected cell culture. microscopy to see the viruses. In other cases, light © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Figure 6-14 Examples of cell inclusions and cytopathic effects Bright-field microscopy of stained cells showing cell inclusions (A) and the cytopathic effect (B) of a virus infection. © JonesA: Courtesy & Bartlett of Skip Van Orden/CDC; B:Learning, Courtesy of Brian W.J. Mahy, LLCBSc, MA, PhD, ScD, DSc/CDC. © Jones & Bartlett Learning, LLC

NOT FOR SALE ORA InDISTRIBUTION a stained brain tissue specimen from a NOTB FORIn this stainedSALE human OR tissue DISTRIBUTION specimen, a rabies patient, the presence of inclusion giant, multinucleated endothelial cell can be bodies called Negri bodies (magenta ovals) seen (arrow), indicative of an infection by are diagnostic for rabies. (Bar = 10 µm) the Paramyxoviridae. (Bar = 10 µm)

9781284240535_CH06_137_168.indd 156 30/12/20 4:55 PM KEY CONCEPT 6-6 Some Viruses Are Associated with Human Tumors and Cancers 157

© Jones & BartlettTable 6-2 Learning, Examples LLC of Virus Inclusion Bodies and© Jones Cytopathic & Bartlett Effects Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALEVirus OR Family DISTRIBUTION Inclusion Bodies Adenoviridae Virions in nucleus Herpesviridae Nuclear granules Poxviridae © Jones & Bartlett Learning, LLC“Viral factories” in cytoplasm© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Rhabdoviridae Virions in cytoplasm (Negri bodies) Cytopathic Effects Adenoviridae, Coronaviridae, Herpesviridae, Rounding and detachment of cells from culture ©Picornaviridae, Jones & Bartlett Rhabdoviridae Learning, LLC © Jones & Bartlett Learning, LLC NOTHerpesviridae FOR SALE OR DISTRIBUTION ChromosomeNOT breakage FOR SALE OR DISTRIBUTION Papovaviridae Cytoplasmic vacuoles Paramyxoviridae Cell fusion (syncytia) © Jones & BartlettPicornaviridae Learning, LLC © JonesShrinking & Bartlett of cell nucleus Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Cancer is indiscriminate. It affects humans and ani- Additional changes can occur to tumor cells. mals,© Jones young & and Bartlett old, male Learning, and female, LLC rich and poor. The tumor© Jones cells might & Bartlett break out Learning, of the capsule LLC and Worldwide,NOT FOR 9.5 SALE million OR people DISTRIBUTION died of cancer in 2019, metastasizeNOT ,FOR a spreading SALE of OR the DISTRIBUTIONcells to other tissues two-thirds in developing nations. In the United States, of the body. Such a tumor is described as malignant, more than 610,000 people died of cancer in 2019, and the individual now has cancer (cancer = “crab”; making the disease the third leading cause of death a reference to the radiating spread of cells, which re- after heart disease and stroke. Cancer is an extraordi- sembles a crab). © Jones & Bartlettnarily complex Learning, topic, LLCso we will only summarize ©the Jones &How Bartlett can such Learning, a mass ofLLC cells bring illness and NOT FOR SALEgeneral OR concept DISTRIBUTION and then emphasize the importantNOT FORmisery SALE to the OR body? DISTRIBUTION By their sheer numbers, cancer points related to viruses. cells invade and erode local tissues, interrupt normal functions, and choke organs to death by robbing them Cancer Is an Uncontrolled of vital nutrients. Thus, the cancer patient will com- © Jones & Bartlett Learning, LLCmonly experience weight© lossJones even &while Bartlett maintaining Learning, LLC Growth andNOT Spread FOR SALE of Cells OR DISTRIBUTIONa normal diet. NOT FOR SALE OR DISTRIBUTION Cancer results, in part, from the uncontrolled reproduction (mitosis) of a single cell. The cell es- capes the cell reproduction control factors and, as Oncogenic Viruses Influence it continues to multiply, a mass of cells soon forms. Cancer Development Eventually,© Jones &the Bartlett cluster yieldsLearning, a clone LLC of abnormal Many cancer© Jones researchers & Bartlett believe Learning, that about LLC 65% of cellsNOT referred FOR SALEto as a tumorOR DISTRIBUTION. Normally, the body will all humanNOT cancers FOR SALEare the ORresult DISTRIBUTION of genetic factors respond to a tumor by surrounding it with fibrous (Figure 6-15). Many of the remaining cancers are as- connective tissue. Such a local tumor is designated sociated with carcinogens, which are chemical and benign because it usually does not spread to sur- physical agents that produce cellular changes leading © Jones & Bartlettrounding Learning, tissue. LLC © Jonesto &a tumorBartlett and Learning,cancer. LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 157 30/12/20 4:55 PM 158 Chapter 6 The Viruses and Other Infectious Agents

The onset of cancer growth patterns of normal cells takes place. This cel- © JonesFigure & Bartlett 6-15 Learning, LLC © Jones & Bartlett Learning, LLC Viruses and other factors can induce a normal cell lular transformation involves a complex, multistep NOT FORto become SALE abnormal. OR DISTRIBUTION When the immune system is NOTsequence FOR SALEof events, OR of DISTRIBUTION which viruses play one part. effective, it destroys abnormal cells. However, when Immune system activity, chronic inflammation, and the abnormal cells evade the immune system, a tumor mutagens usually are additional factors required for might develop and become malignant, spreading to other tissues in the body. Provide some examples of malignant transformation. chemical and physical carcinogens.© Jones & Bartlett Learning, LLCAs Table 6-3 shows, oncogenic© Jones viruses & Bartlettare found Learning, LLC EnvironmentalNOT carcinogens FOR SALE OR DISTRIBUTIONonly in some families of DNANOT viruses FOR (DNA SALE tumor OR DISTRIBUTION viruses), which have dsDNA genomes, and Retrovir- idae (RNA tumor viruses), which have dsDNA when integrated as a provirus in a host cell. The most com- © Jones & Bartlett Learning, LLC mon virus-associated© Jones malignancy & Bartlett among Learning, women LLC is uterine cancer, which is caused by specific groups Genetic VirusesNOT FORRadiation SALE ORChemicals DISTRIBUTION NOT FOR SALE OR DISTRIBUTION factors of human papillomaviruses (HPVs) in the Papova- viridae. In men, liver cancer, caused by the hepatitis B virus (Hepadnaviridae), is the most common. One further point is that there might be other, yet © Jones & Bartlett Learning, LLCNormal cell © Jonesunidentified & Bartlett viruses Learning,that also are LLCassociated with hu- NOT FOR SALE OR DISTRIBUTION NOTman FOR cancers. SALE OR DISTRIBUTION On the positive side, individuals can be vacci- nated to prevent infection by HPV and hepatitis B virus, and antiviral drugs are available that reportedly © Jones & Bartlett Learning,can LLC cure hepatitis C infections.© JonesThus, the & incidencesBartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONof cancer caused by these virusesNOT have FOR been SALE declining. OR DISTRIBUTION Abnormal cell and tumor formation Oncogenic viruses are thought to cause tumors in three ways: Immune Immune • Oncogene Activity. One way the cellular trans- system ineffective system effective © Jones & Bartlett Learning, LLC formation© processJones &is Bartlettmediated Learning,is by proteins LLC NOT FOR SALE OR DISTRIBUTION encoded NOTby oncogenes FOR SALE, which OR areDISTRIBUTION viral genes Destruction of possessed by some members of the Retroviri- Cancer abnormal cell dae. Upon infection of a human cell, integration and expression of the viral oncogene convert a normal cell into a tumorous or cancerous cell © Jones & InBartlett 1911, Francis Learning, Payton LLC Rous, a virologist, was © Jones(Figure & Bartlett 6-16A). TheseLearning, genes LLCusually affect cell NOT FORstudying SALE breast OR cancerDISTRIBUTION in chickens. In his studies, he NOT FORdivision SALE or the OR chemical DISTRIBUTION signaling involved in discovered that when he took a bacterial- and cell-free cell growth. extract from a chicken breast cancer and transferred • Gene Suppression. Cellular transformation can it to healthy chickens, the recipients would develop occur through the loss of normal gene activity. breast cancer. Eventually© a Jones virus, now & Bartlett called the Learning, Rous LLCNormal cells contain several© Jones tumor &suppressor Bartlett Learning, LLC sarcoma virus, was discovered as the agent triggering , the function of which is to inhibit NOT FOR SALE OR DISTRIBUTIONgenes (TSGs) NOT FOR SALE OR DISTRIBUTION the cancer. transformation by triggering a programmed cell Today, health experts suspect that about 12% of death (cell suicide) called apoptosis. However, if human cancers globally are associated with viruses, a provirus integrates near a TSG, the close asso- the majority caused by human papillomaviruses ciation with the TSG can bring about the loss of (HPVs;© 690,000 Jones new& Bartlett cases each Learning, year), the LLC hepati- TSG control,© Jones resulting & Bartlettin uncontrolled Learning, cell divi LLC- tis B virusNOT (360,000 FOR SALE new casesOR DISTRIBUTIONeach year), and the sions (FigureNOT 6-16B FOR). SALE OR DISTRIBUTION hepatitis C virus (160,000 new cases each year). In • Gene Activation. If a provirus integrates near all, at least six viruses are associated directly or in- a gene to stimulate cell division, the close asso- directly with human tumors and cancers (Table 6-3). ciation might permanently “turn on” the gene © JonesWhen & Bartlett these oncogenic Learning, (tumor-causing) LLC viruses are © Jonesand &the Bartlett synthesis Learning, of growth-promoting LLC pro- NOT FORtransferred SALE toOR test DISTRIBUTION animals or cell cultures, an observ- NOT FORteins, SALEagain leading OR DISTRIBUTION to uncontrolled cell division able change in the morphological, biochemical, or (Figure 6-16C).

9781284240535_CH06_137_168.indd 158 30/12/20 4:55 PM KEY CONCEPT 6-6 Some Viruses Are Associated with Human Tumors and Cancers 159

© Jones & BartlettTable 6-3 Learning, Viruses Involved LLC with Human Cancer© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALEVirus OR Family DISTRIBUTION Notable Vaccine Type Some Effects Malignancies Other Diseases Available? dsDNA Tumor Viruses Papillomaviridae © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC ■ Human NOT FOROncogene SALE expres- OR DISTRIBUTIONCervical carcinoma Benign wartsNOT FORYes SALE (malignancy OR DISTRIBUTION papillomavirus (HPV) sion encodes proteins Penile cancer Genital warts and genital warts that inactivate tumor Oropharyngeal infections only) suppressor genes cancer and stimulate cell © Jones & Bartlett Learning,proliferation LLC © Jones & Bartlett Learning, LLC NOTPapovaviridae FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION ■ Merkel cell polyoma Being investigated Merkel cell Unknown No virus (MCPV) carcinoma Herpesviridae © Jones & Bartlett ■ Epstein-Barr Learning, virus LLCOncogene expression ©Burkitt Jones lymphoma & BartlettInfectious Learning, LLC No NOT FOR SALE(EBV) OR DISTRIBUTIONencodes proteins that NOTHodgkin FOR lymphoma SALE ORmononucleosis DISTRIBUTIONNo inactivate cell growth Nasopharyngeal Gastric carcinoma regulatory proteins carcinoma and stimulate cell proliferation ■ Human herpesvirus© Jones Oncogene & Bartlett expres- Learning,Kaposi LLC sarcoma Unknown© Jones & Bartlett Learning, LLC 8 (HHV8) NOT FORsion SALE stimulates OR cell DISTRIBUTION Lymphomas NOT FOR SALE OR DISTRIBUTION proliferation and blood vessel growth Hepadnaviridae © ■ JonesHepatitis & B Bartlettvirus Learning,Encodes a protein LLC that Hepatocellular © JonesHepatitis & Bartlett Learning,Yes LLC NOT(HBV) FOR SALE OR DISTRIBUTIONstimulates cell prolif- carcinoma (HCC)NOT FORCirrhosis SALE OR DISTRIBUTION eration and promotes blood vessel growth ssRNA Tumor Viruses © Jones & BartlettFlaviviridae Learning, LLC © Jones & Bartlett Learning, LLC Virus causes hepatic Hepatocellular car- Hepatitis No NOT FOR SALE ■ Hepatitis OR DISTRIBUTION C virus NOT FOR SALE OR DISTRIBUTION (HCV) damage, inflammation, cinoma (HCC) Cirrhosis and blood vessel growth

Retroviridae ■ Human T-cell Oncogene expression Adult T-cell Weakness of the No lymphotropic virus-1© Jones encodes & Bartlett proteins Learning, that leukemia LLC (ATL) legs © Jones & Bartlett Learning, LLC (HTLV-1) NOT FORactivate SALE cell ORprolifera- DISTRIBUTION NOT FOR SALE OR DISTRIBUTION tion and chromosomal instability

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION This ability of viruses to get inside cells and Tumor Viruses Do Not Always deliver their viral information or influence host Cause Cancer cell genetic information has been manipulated by Not everyone infected with an oncogenic virus devel- © Jones & Bartlettresearch Learning,scientists to LLC deliver genes to cure genetic© Jones ops & cancer.Bartlett Human Learning, cells have LLC division controls and NOT FOR SALEillnesses. OR MicroFocusDISTRIBUTION 6-3 looks at using viruses NOTfor FORcheckpoints SALE OR that DISTRIBUTION must be disrupted for malignant this purpose. transformation to occur. In fact, a variety of factors,

9781284240535_CH06_137_168.indd 159 30/12/20 4:55 PM 160 Chapter 6 The Viruses and Other Infectious Agents

Figure 6-16 Tumor viruses and tumor induction © JonesSome & Bartlett viruses can Learning, be associated LLC with tumor development through© Jones oncogene & Bartlett activity ( ALearning,), inactivation LLC of genes (B), or NOT FORactivation SALE of ORgenes DISTRIBUTION (C). What advantage is it to the tumor virusNOT to cause FOR cells SALE to divide OR endlessly? DISTRIBUTION

A Some oncogenic viruses carry an oncogene whose protein product directly causes uncontrolled growth.

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Virus oncogene Virus-infected active DNA/RNA Abnormal Uncontrolled cell growth cell tumor virus cell and division (tumor)

©B JonesOther viruses & Bartlett integrate their Learning, DNA next to aLLC tumor suppressor gene (TSG), resulting© Jones in inactivation & Bartlett of the TSG Learning, and LLC NOTleading FOR to uncontr SALEolled OR cell grDISTRIBUTIONowth. NOT FOR SALE OR DISTRIBUTION

Inactive © Jones & Bartlett Learning, LLCVirus-infected TSG © Jones & Bartlett Learning, LLC Abnormal Uncontrolled cell growth DNA/RNA cell (+TSG) NOT FOR SALE OR DISTRIBUTION NOTcell FOR SALE OR DISTRIBUTIONand division (tumor) tumor virus

C Yet other viruses integrate their DNA next to a silent growth control gene, resulting in activation of the gene and uncontrolled growth. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Silent gene activated Virus-infected Abnormal Uncontrolled cell growth DNA/RNA cell cell and division (tumor) tumor virus © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION MicroFocus 6-3 The Power of the Virus

© Jones Ever& Bartlett since virologists Learning, understood LLC how viruses infect cells ©and Jones replicate, & theyBartlett have wondered Learning, how LLCviruses could be used to cure disease, such as some forms of cancer. As described in the chapter opener, mutant herpes simplex NOT FORviruses SALE have OR been DISTRIBUTION developed that can kill the cancer cellsNOT they infect FOR and SALE stimulate OR the DISTRIBUTION immune system to attack the cancer. Used on patients with terminal melanoma, the virotherapy often has been successful in sending the cancer into remission or apparently curing the patient of the cancer. In 2015, the FDA approved the use of this therapy, called TVEC, for the treatment of late-stage melanomas that doctors cannot remove through surgery. Other human viruses also are being used for so-called virotherapy. In 2018, scientists at the Duke Cancer Institute reported on the© use Jones of a genetically & Bartlett modified Learning, polio virus LLC to attack a rare but aggressive© Jonesand deadly & brainBartlett Learning, LLC cancer called glioblastoma.NOT This FOR is the SALE disease OR that DISTRIBUTION took the life of Senator Ted Kennedy and recentlyNOT FOR Senator SALE OR DISTRIBUTION John McCain. In patients taking part in the clinical trials, the modified polio virus was injected directly into the tumor where it began to kill the tumor. More importantly, as with TVEC, it triggered the immune system to attack the cancer and destroy additional cancer cells. The glioblastoma patients showed a 3-year survival rate of 21% compared with just 4% for patients given standard therapy. Additional “oncolytic” (cancer-killing) viruses are being developed.© Jones Today, & research Bartlett into Learning, virotherapy is LLC in high gear, with many early ©clinical Jones trials & in Bartlett progress toLearning, examine the LLC powerNOT of viruses FOR to SALE attack and OR kill DISTRIBUTION cancer cells directly or indirectly. The futureNOT for FORvirotherapy SALE is looking OR DISTRIBUTION promising.

including environment, diet, and lifestyle, as well as host genetics contribute to the transformation pro- © Jonescess. & BartlettIn addition, Learning, immune LLC system status and sur- © JonesConcept & Bartlett Check Learning,6-6 LLC NOT FORveillance SALE are OR critical DISTRIBUTION in determining if cancer might NOT FOR SALE OR DISTRIBUTION 15. Describe the three ways that an oncogenic virus develop (see Figures 6-15 and 6-16). Thus, tumor vi- might cause a tumor. rus infection is only one part of cancer development.

9781284240535_CH06_137_168.indd 160 30/12/20 4:56 PM KEY CONCEPT 6-7 Emerging Viruses Arise from Genetic Recombination and Mutation 161

Almost every year, a newly emerging influenzavirus de- One way “new” viruses arise is through genetic scends upon the human© Jones population. & Bartlett Other Learning, viruses not LLCrecombination. Take,© for Jones example, & Bartlett influenza. Learning, The LLC even heard of a fewNOT decades FOR ago, SALE such asOR HIV, DISTRIBUTION Ebolavi- mixing (reassortment) ofNOT genes FOR between SALE different OR DISTRIBUTION in- rus, West Nile virus, Zika virus, and SARS-CoV-2 often fluenzaviruses generates new flu strains every season are in the news. Where are these viruses coming from? in both the Northern and Southern Hemispheres. The “swine flu” pandemic that broke out in Mexico in 2009 was the result of the reassortment of genome © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Emerging Viruses Usually Arise segments from a strain of avian flu virus, a human flu ThroughNOT FOR SALE Natural OR DISTRIBUTION Phenomena virus, andNOT a swine FOR flu SALE virus. OR DISTRIBUTION The human population is at greater risk than ever Viruses also arise from a second force driving evo- from zoonotic diseases, which are animal diseases lution—mutation, which is a permanent alteration capable of being transmitted from animals to humans in the genome of the organism or virus. For example, © Jones & Bartlett(Table 6-4 Learning,). In fact, 70% LLC of human infections come© Jones in &a replicatingBartlett Learning,RNA virus genome, LLC the virus is poorly NOT FOR SALEfrom ORpathogens DISTRIBUTION originally found in other animals.NOT FORequipped SALE to OR “proofread” DISTRIBUTION and correct any mistakes Many of these emerging infectious diseases, like when replicating its genome. Occasionally, a mutation COVID-19, are the result of viruses appearing for the might show up and be advantageous. In the case of first time in the human population or rapidly expand- SARS-CoV-2, HIV, and influenzaviruses, a beneficial ing their host range with a corresponding increase in © Jones & Bartlett Learning, LLCmutation might have generated© Jones a new & Bartlett virus strain Learning, ca- LLC detectable disease. Many, including SARS-CoV-2, are pable of infecting humans. With a rapid replication NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION transmitted by bats while other viral pathogens are rate and burst size, it does not take long for a benefi- transmitted by insect vectors, such as ticks, fleas, or cial mutation to establish itself within a population. mosquitoes. One example of the latter transmission is Even if a new virus has emerged, it must en- the West Nile virus that is carried by mosquitoes. The counter an appropriate host in which to replicate disease© Jones spread & Bartlettacross the Learning,United States LLC between 1999 and spread.© Jones It is believed & Bartlett that smallpoxLearning, and LLC measles andNOT 2009 FOR and SALE now is OR endemic DISTRIBUTION (prevalent) across the both evolvedNOT FORfrom cattleSALE viruses, OR DISTRIBUTION whereas flu proba- continental United States. bly originated in ducks and pigs. HIV almost certainly But no matter how these viruses are transmitted, evolved from a monkey (simian) immunodeficiency what caused their emergence? virus and SARS-CoV-2 from a coronavirus in bats. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Table 6-4 Examples of Emerging Zoonotic Viruses Virus Genome Emergence Factor Chikungunya © Jones −ssRNA& Bartlett Spread Learning, through newLLC mosquito vectors and global© Jones travel & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Ebola/Marburg −ssRNA Human contact with infected fruit bats

HIV +ssRNA Contact with infected apes/monkeys in Africa Influenza −ssRNA Mixed pig and duck agriculture, mobile population © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Lassa −ssRNA Human contact with infected rodents NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Nipah/Hendra −ssRNA Human contact with infected flying foxes (bats)

SARS-CoV-2 +ssRNA Contact with infected bats or an infected intermediary animal Sin Nombre (hantavirus) −ssRNA Large, infected deer mice population and contact with humans © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEWest OR Nile DISTRIBUTION+ssRNA Infected mosquitosNOT FOR transported SALE unknowingly OR DISTRIBUTION by global travel Zika +ssRNA Contact with infected mosquitoes carried from Africa and South Pacific

9781284240535_CH06_137_168.indd 161 30/12/20 4:56 PM 162 Chapter 6 The Viruses and Other Infectious Agents

Consequently, at some time such viruses had to make emerging viral disease. The spring of 1993 the Amer- © Jones & Bartlett Learning, LLC © Jonesa species& Bartlett jump. Learning, What could LLCfacilitate such a jump? ican Southwest experienced a wet season, resulting in NOT FOR SALEOur proximity OR DISTRIBUTION to wild and domestic animals and NOTample FOR food SALE for deer OR mice. DISTRIBUTION The expanding deer mouse their pathogens makes such a jump possible. Today, population brought the mice into closer contact with population pressure is pushing the human population humans. Leaving behind mouse feces and dried urine into more remote areas of the world where potentially containing the hantavirus made infection in humans virulent viruses might ©be Jones endemic. & EvidenceBartlett showsLearning, likely. LLC The deaths of 14 people© withJones a mysterious & Bartlett re- Learning, LLC the Machupo and JuninNOT viruses FOR (Arenaviridae SALE OR viruses DISTRIBUTION spiratory illness in the Four CornersNOT FOR area SALEthat spring OR DISTRIBUTION that cause hemorrhagic fevers in South America) eventually were attributed to this newly recognized jumped from rodents to humans because of increased virus. agricultural practices that, for the first time, brought Therefore, emerging viruses are not new. They are infected© rodents Jones into & Bartlettcontact with Learning, humans. LLC simply evolving© Jones from existing & Bartlett viruses, Learning, and, through LLC The COVID-19 pandemic started out as an un- human activity or interactions with the environment, NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION usual pneumonia in Southeast Asia. The mixing of these viruses are given the “opportunity” to spread or potentially virus-infected live and dead slaughtered to increase their host range. animals, and their close proximity to humans in the trading markets might have provided an ideal en- © Jonesvironment & Bartlett for Learning,the virus to LLCjump species. Or did it? © JonesConcept & Bartlett Check Learning,6-7 LLC NOT FORClinical SALE Case OR 6 examines DISTRIBUTION possible origins. NOT FOR SALE OR DISTRIBUTION 16. Identify the ways that emerging viral diseases An increase in the size of the animal host popula- arise. tion carrying a viral disease also can “explode” as an

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Clinical Case 6 Identifying a Virus and Its Origins On December© Jones 31, & 2019, Bartlett Chinese Learning, authorities alerted LLC A typical Chinese© wet Jones market. & Bartlett Learning, LLC the WorldNOT Health FOR Organization SALE OR (WHO) DISTRIBUTION of a mysterious © Gwoeii/Shutterstock. NOT FOR SALE OR DISTRIBUTION pneumonia-like outbreak in Wuhan, a city of 11 million people. Patients were quarantined. Chinese health experts quickly identified a Wuhan wet market as one probable source of the outbreak. These markets consist of crowded outdoor © Jones stalls& Bartlett where locals Learning, and visitors LLC shop for all types © Jones & Bartlett Learning, LLC NOT FORof SALE products, OR including DISTRIBUTION meat, fish, produce, caged NOT FOR SALE OR DISTRIBUTION chickens, and skinned animals (see figure). The market was closed on January 1, 2020. One week later, through genome sequencing, the outbreak was found to be due to a novel coronavirus. Scientists identified© the Jones first human & Bartlett coronavirus Learning, LLC © Jones & Bartlett Learning, LLC in 1965. It was an infectiousNOT agent FOR causing SALE a versionOR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION of the common cold. Later that decade, researchers found a group of similar human and animal viruses and placed them in their own family named the Coronaviridae (corona = “crown”) after their crown-like appearance. In 2002, one coronavirus that caused severe acute© respiratory Jones & syndrome Bartlett (SARS) Learning, emerged LLCin southern China and quickly© spread Jones to 28 & otherBartlett countries. Learning, Many of LLC the earlyNOT case-patients FOR SALE reported OR DISTRIBUTIONliving near a produce market in Foshan municipality,NOT FOR Guangdong SALE OR Province, DISTRIBUTION China. Spreading to several parts of the world, the virus caused more than 8,000 infections and 774 died from SARS. In 2012, another coronavirus outbreak occurred in Saudi Arabia. Called the Middle Eastern respiratory syndrome (MERS), nearly 2,500 cases were reported in people who lived in or traveled to the Middle East. This coronavirus killed 858 people, primarily in the Middle East. © Jones & BartlettWithin a week Learning, after the firstLLC announcement of the Wuhan© Jones outbreak, & the Bartlett viral genome Learning, had been LLC sequenced NOT FORand SALE identified OR as DISTRIBUTION a new coronavirus, similar to the SARS virusNOT but FOR unique SALE enough OR that DISTRIBUTION five weeks later it was given its own name, the sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease was

9781284240535_CH06_137_168.indd 162 30/12/20 4:56 PM KEY CONCEPT 6-8 Prions Are Noncellular Infectious Agents 163

© Jones & Bartlettcalled coronavirus Learning, disease LLC 2019 (COVID-19). Since ©its Jonesdiscovery, & the Bartlett disease hasLearning, continued LLCto spread worldwide, NOT FOR SALEparalyzing OR DISTRIBUTION economies and social interactions. NOT FOR SALE OR DISTRIBUTION Originally, it was thought SARS-CoV-2 jumped to humans from an animal host at a Wuhan wet market, as the majority of cases could be traced back to the market. The thought was that the virus was present in an animal sold at the market. Because the natural host of the Coronaviridae appears to be bats, and bats were not at the market, another animal harboring the virus might have been an “intermediary” in passing the virus to humans. As further studies© Jones were carried& Bartlett out on Learning,the transmission LLC of SARS-CoV-2, it became© clear Jones that some & Bartlett of the first Learning, LLC cases of COVID-19NOT had FORno link SALE to the wet OR market. DISTRIBUTION People in Shanghai, China were infectedNOT early FOR in theSALE outbreak OR but DISTRIBUTION had no connection to the Wuhan wet market, which is over 800 kilometers (500 miles) to the west. When SARS-CoV-2 samples from patients in Wuhan and Shanghai were compared, the “wet market virus” had a slightly different nucleotide sequence from that in the “Shanghai virus.” This would suggest two origins for human infections. However, both probably originated through mutations from a “common viral ancestor” that caused the ©first Jones human & cases Bartlett (unreported) Learning, in November LLC or early December 2019.© Jones & Bartlett Learning, LLC Both viruses are extremely similar and appear to not vary in the disease severity they cause. People with mild NOTsymptoms FOR (fever SALE and ORlung DISTRIBUTIONinflammation) or severe disease (difficultyNOT breathing FOR and SALE lung damage) OR DISTRIBUTION could have either of the two virus strains. Rather, disease severity seems to be based on other factors, such as age, preexisting medical conditions, and gender. Questions © Jones & Bartlett1. Could Learning, SARS-CoV-2 LLC have been identified as a member© Jones of the & Coronaviridae Bartlett Learning, without sequencing LLC its genome? NOT FOR SALE Explain?OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 2. What does it mean to say that SARS-CoV-2 jumped to humans? 3. How might a risk analysis of disease have changed if a dual origin for SARS-CoV-2 had been known from the outset of the outbreak? 4. What biological process could have given rise to the two SARS-CoV-2 forms coming from the ancestral virus? 5. Was the wet market© Jones in W uhan& Bartlett the origin Learning, of the pandemic? LLC Explain © Jones & Bartlett Learning, LLC You can find answersNOT online FOR in SALE Appendix OR E. DISTRIBUTION NOT FOR SALE OR DISTRIBUTION For additional information on the early epidemic in the United States, see https://www.cdc.gov/mmwr/volumes /69/wr/mm6924e2.htm?s_cid=mm6924e2_w

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION KEY CONCEPT 6-8 Prions Are Noncellular Infectious Agents © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC When viruses were discovered, scientists believed A connection between mad cow disease and a NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION they were among the smallest infectious particles. similar human disease surfaced in Great Britain in It was difficult to conceive of anything smaller than 1995 when several young people died of a human viruses as agents of infectious disease. However, the brain disorder resembling mad cow disease. Symp- perception was revised as scientists discovered new toms included dementia, weakened muscles, and loss disease agents—the© Jones subviral & particles Bartlett referred Learning, to as LLCof coordination. Health ©officials Jones suggested & Bartlett the humanLearning, LLC prions (pronouncedNOT “pree-ons”). FOR SALE OR DISTRIBUTIONdisease was caused by eatingNOT beefFOR that SALE had been OR proDISTRIBUTION- cessed from cattle with mad cow disease. The disease agent had been transmitted from cattle to humans. Prions Are Infectious Proteins Besides mad cow disease, similar neurological de- In© 1986,Jones cattle & Bartlett in Great Learning,Britain began LLC dying from a generative© Jones diseases & have Bartlett been discovered Learning, and LLC studied mysteriousNOT FOR illness. SALE The OR cattle DISTRIBUTION experienced weight loss, in otherNOT animals FOR and SALE humans. OR These DISTRIBUTION include scrapie became aggressive, lacked coordination, and were in sheep and goats, chronic wasting disease in elk unsteady in their gait. These harmful effects became and deer, and Creutzfeldt-Jakob disease in humans. known as mad cow disease, which was responsible All are examples of a group of rare diseases called for the eventual death of more than 180,000 infected transmissible spongiform encephalopathies © Jones & Bartlettcattle. More Learning, than 4.4 LLC million cattle in Great Britain© Jones (TSEs) & Bartlett because, Learning, like mad cow LLC disease (bovine spon- NOT FOR SALEwere ORslaughtered DISTRIBUTION to prevent further spread of NOTthe FORgiform SALE encephalopathy; OR DISTRIBUTION BSE), they can be transmitted disease. to other animals of the same species and possibly to

9781284240535_CH06_137_168.indd 163 30/12/20 4:56 PM 164 Chapter 6 The Viruses and Other Infectious Agents

other animal species, including humans. The disease roles to play in everything from neuron protection to © Jones & Bartlett Learning, LLC © Jonescauses & Bartlett the formation Learning, of sponge-like LLC holes in brain tis- learning during infant development. Only when these NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION sue (Figure 6-17A). proteins undergo mutation do they become abnormal, Many scientists originally believed these agents misfolded prions (PrPSc). In fact, in 2004, Prusiner’s were a new type of virus. However, in the early 1980s group showed that purified PrPSc could cause disease Stanley Prusiner and colleagues isolated an unusual when injected into the brains of healthy mice. protein from scrapie-infected© Jones tissue & ofBartlett sheep, whichLearning, LLCToday, many researchers ©believe Jones TSEs & areBartlett spread Learning, LLC they believed was the infectiousNOT FOR agent. SALE Prusiner OR called DISTRIBUTION by the infectious PrPSc being takenNOT upFOR intact SALE from theOR DISTRIBUTION the proteinaceous infectious particle a prion. digestive tract and transported to the nervous tissue This led Prusiner to propose the protein-only where they accumulate in the central nervous sys- C hypothesis, which states that prions are small, tem. The particles then bind to normal PrP , caus- self-replicating© Jones proteins & Bartlett devoid Learning, of any nucleic LLC acid ing the latter ©to Joneschange shape& Bartlett (Figure Learning, 6-18). Through LLC genome. The protein-only hypothesis further pro- a domino-like (autocatalytic) effect, the newly con- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION poses that there are two types of prion proteins verted PrPSc proteins, in turn, cause more PrPC C (Figure 6-17B). Normal neural cellular prions (PrP ) proteins to become abnormal. Eventually, the accu- are found in brain and nerve tissue and have important mulation of PrPSc proteins forms insoluble protein fibers that aggregate, forming sponge-like holes left © JonesFigure & Bartlett 6-17 Prion Learning, “infection” LLC and structure © Joneswhere groups & Bartlett of nerve Learning, cells have LLCdied. Importantly, NOT FORNerve SALE cell destruction OR DISTRIBUTION (A) can result from the shape NOTPrP FORSc does SALE not trigger OR an DISTRIBUTION immune response and loss of change of prions (B). Identify the secondary structures life occurs from nerve cell damage and brain atrophy. (alpha-helices and pleated sheets) in (B). The human form of TSE appears similar to the A: Courtesy of Teresa Hammett/CDC. classic and spontaneous form of Creutzfeldt-Jakob A Light microscopy of a stained© Jones section of & human Bartlett brain tissue Learning, disease LLC (CJD). The new prion-derived© Jones form & Bartlett of CJD, Learning, LLC from vCJD individual showing the vacuolar (“spongy”) called variant CJD (vCJD), is characterized clini- degeneration (clear areas)NOT caused FOR by prior SALE infection. OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION cally by neurological abnormalities such as dementia.

Figure 6-18 Prion formation and propagation © Jones & Bartlett Learning, LLC Prion proteins© (PrP JonesSc) bind & to Bartlett normal prion Learning, precursors LLC NOT FOR SALE OR DISTRIBUTION (PrPC) in neurons,NOT causing FOR these SALE proteins OR DISTRIBUTIONto take on a misfolded PrPSc conformation. This process is repeated (replicated) many times, leading to the accumulation of PrPSc protein fibers that cause progressive neuron cell death. © Jones & Bartlett Learning, LLC © JonesNeuron & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION PrPc Sc PrP 1 A prion protein (PrPSc) interacts with a normal prion (PrPc). © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION 2NOT FOR SALE OR DISTRIBUTION B The teriary structure of the normal prion protein [left] The PrPc is converted and a misfolded prion [right]. to PrPSc.

3 Additional PrPSc © Jones & Bartlett Learning, LLC © Jones & Bartlettconvert Learning, more PrPc into LLC Sc NOT FOR SALE OR DISTRIBUTION NOT FOR SALEPr POR. DISTRIBUTION

4 PrPc throughout the neuron are converted into PrPSc. As the © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning,neurons LLC die, vacuolar NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTIONareas form in the gray matter. PrPC PrPSc

9781284240535_CH06_137_168.indd 164 30/12/20 4:56 PM Chapter Review 165

Neuropathology shows a marked spongiform appear- include condemning those animals having signs of © Jones & Bartlett Learning, LLC © Jones & Bartlettance throughout Learning, the brain, LLC and death occurs within 3 neurological illness and holding any cows suspected of NOT FOR SALEto 12 ORmonths DISTRIBUTION after symptoms appear. NOT FORhaving SALE BSE ORuntil DISTRIBUTION test results are known. In addition, The number of confirmed and probable deaths “downer cattle”—those unable to walk on their own— from vCJD peaked in 2000 and then slowly dropped cannot be used for human food or animal feed. off. In all, about 177 vCJD deaths occurred in the United Kingdom ©and Jones 27 more & Bartlettin France. Learning,No cases of LLC © Jones & Bartlett Learning, LLC vCJD from infectedNOT cattle FOR in the SALE United StatesOR DISTRIBUTION have been Concept Check 6-8NOT FOR SALE OR DISTRIBUTION reported. Experts believe BSE is almost extinct because 17. How are prions (a) similar to and (b) different the last reported case in cattle in the United Kingdom from viruses? was in 2012. To keep it that way, protection measures © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION As a Final Point . . .

The fossil record has been useful to study the origins Cellular Origins Hypothesis. Viruses are derived © Jones & Bartlett Learning, LLC © Jones• & Bartlett Learning, LLC of plants and animals, and even some members of the from subcellular components (DNA and RNA) NOT FOR SALEdomain OR Bacteria. DISTRIBUTION Even though there is no fossil recordNOT FOR SALEand functional OR DISTRIBUTION assemblies of macromolecules that for the viruses, scientists and virologists have pro- escaped from cells and evolved into particles that posed three hypotheses to explain how viruses might could replicate in host cells. have originated. • Coevolution Hypothesis. Viruses arose at the © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC • Regressive Evolution Hypothesis. Viruses are same time as cellular life and transitioned to a degenerate lifeNOT forms; FOR that SALE is, they OR are DISTRIBUTION derived parasitic form by hijackingNOT FOR the cellular SALE machinery OR DISTRIBUTION from small cells that functioned as intracellular of the newly evolving organisms. parasites. Over time, the cells lost many functions Although each of these theories has its support- that could be supplied by their hosts, and the life ers, the topic generates strong disagreements among © Jonesforms retained & Bartlett only thoseLearning, genes essentialLLC for di- experts.© To Jones date, no & clear Bartlett explanation Learning, for the LLCorigin(s) NOTrecting FOR their SALE parasitic OR wayDISTRIBUTION of life. of virusesNOT exists. FOR SALE OR DISTRIBUTION

Summary of Key Concepts © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 6-1 Filterable Infectious Agents surrounded by a protein capsid, and many NOT FOR SALE OR DISTRIBUTION viruses have an NOT FORsurrounding SALE the OR DISTRIBUTION Cause Disease envelope nucleocapsid. Spikes protruding from the 1. The concept of a virus as a filterable agent of capsid or envelope are used for attachment to disease was first suggested by Ivanowsky. Twort host cells. (Figure 6-3) and d’Herrelle identified viruses as infective 3. Viruses have helical, icosahedral, or complex © Jonesagents in & bacterial Bartlett organisms. Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION symmetryNOT FOR. (Figure SALE 6-4) OR DISTRIBUTION 4. Viruses can be transmitted by direct or indirect contact transmission or in airborne particles 6-2 Viruses Have a Simple Structural as aerosols and droplets. The host range of a Organization virus refers to what organisms (host cells) the © Jones & Bartlett2. Viruses Learning, are composed LLC of nucleic acid (DNA © Jones &virus Bartlett can infect. Learning, Many viruses LLC infect only certain NOT FOR SALEor OR RNA) DISTRIBUTION in either a single-stranded or NOT FOR SALEcell types OR or DISTRIBUTIONtissues within the host referred to as a double-stranded form. The genome is cell/tissue specificity. (Figure 6-5)

9781284240535_CH06_137_168.indd 165 30/12/20 4:56 PM 166 Chapter 6 The Viruses and Other Infectious Agents

© Jones6-3 & Bartlett Viruses Learning, Can Be ClassifiedLLC by © Jones6-6 Some & Bartlett Viruses Learning, Are Associated LLC NOT FOR SALETheir OR Genome DISTRIBUTION NOT FORwith SALE Human OR DISTRIBUTION Tumors and 5. Two broad classes of viruses can be organized Cancers based on their genome and strand type: the 10. The formation of tumors is a complex process single-stranded or double-stranded DNA viruses whereby cells multiply without control and and the single-stranded© Jones or double-stranded & Bartlett Learning,RNA LLCpossibly develop into cancers© Jones. & Bartlett Learning, LLC viruses. The latter NOTmight FORbe either SALE +sense OR or DISTRIBUTION 11. At least seven oncogenicNOT viruses FOR are knownSALE toOR DISTRIBUTION -sense. (Figure 6-6) cause human tumors. Many of these tumors can develop into cancer. (Table 6-3) 6-4 Virus Replication Follows a Set of 12. Viruses can bring about tumors by oncogene activity, inactivating , Common© Jones & Steps Bartlett Learning, LLC © Jones tumor& Bartlett suppressor Learning, genes LLC or activating gene expression. (Figure 6-16) 6. BacteriophagesNOT FOR SALE undergo OR a lyticDISTRIBUTION pathway, NOT FOR SALE OR DISTRIBUTION involving attachment, penetration, biosynthesis, assembly, and release stages, or a lysogenic 6-7 Emerging Viruses Arise from pathway, where the phage genome integrates Genetic Recombination and © Jones & intoBartlett the bacterial Learning, chromosome LLC as a prophage. © JonesMutation & Bartlett Learning, LLC (Figures 6-8 and 6-9) NOT FOR SALE OR DISTRIBUTION NOT13. FORViruses SALE use OR DISTRIBUTION and 7. Animal viruses also progress through the same genetic recombination as mechanisms to evolve. Human stages of replication, but the genome must mutations population expansion into new areas and be uncoated prior to genome replication. increased agricultural practices in previously (Figure 6-10) forested areas have exposed humans to existing 8. Many of the DNA viruses© Jones and the& Bartlett retroviruses Learning, LLC © Jones & Bartlett Learning, LLC animal viruses. can incorporate theirNOT viral FOR DNA SALEindependently OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION within the host’s cell nucleus, or as a provirus. (Figure 6-11) 6-8 Prions Are Noncellular Infectious Agents 6-5 Viruses© Jones and & Bartlett Their Learning,Infections LLC Can 14. Prions are© infectiousJones & particles Bartlett made Learning, only LLC of protein. Prions cause BeNOT Detected FOR SALE in VORarious DISTRIBUTION Ways NOT FOR SALEtransmissible OR DISTRIBUTION by 9. Various detection methods for viruses are based spongiform encephalopathies (TSEs) folding improperly and, in the misfolded on the cultivation of animal viruses using shape, cause other prions to misfold. cell cultures. Viruses can be detected by the (Figures 6-17, 6-18) © Jones & formationBartlett ofLearning, plaques and LLC by observation of © Jones & Bartlett Learning, LLC NOT FOR SALEcharacteristic OR DISTRIBUTION inclusion bodies or cytopathic NOT FOR SALE OR DISTRIBUTION effects.

Chapter Self-Test For more practice quizzes,© assessments,Jones & Bartlettanimations, Learning, vid- LLCFor Steps A–C, you can© find Jones answers & Bartlett to ques- Learning, LLC eos, and other study aids,NOT go online FOR to SALENAVIGATE OR DISTRIBUTION2. tions and problems in AppendixNOT F. FOR SALE OR DISTRIBUTION

STEP A: Recall Read each question or statement carefully before se- 2. Describe a nucleocapsid. lecting© an Jones answer. & Bartlett Learning, LLC 3. An RNA ©virus Jones genome & Bartlettin the form Learning, of messenger LLC 1. ViralNOT genomes FOR consistSALE of: OR DISTRIBUTION RNA is referredNOT FOR to as aSALE _____ ORRNA. DISTRIBUTION A. DNA only. A. +sense B. RNA only. B. double-stranded C. DNA or RNA. C. −sense © Jones &D. Bartlett DNA and Learning, RNA. LLC © JonesD. reverse & Bartlett strand Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284240535_CH06_137_168.indd 166 30/12/20 4:56 PM Chapter Review 167

4. List the five stages of virus replication. 9. Newly emerging viruses causing human disease © Jones & Bartlett Learning, LLC © Jones & Bartlett5. The releaseLearning, of the LLCviral genome from the capsid can arise from: NOT FOR SALEis ORcalled: DISTRIBUTION NOT FOR SALEA. species OR jumping. DISTRIBUTION A. uncoating. B. mutations. B. decomposition. C. genetic recombination C. penetration. D. All of these are correct. D. maturation.© Jones & Bartlett Learning, LLC10. Which of the following© Jones statements & Bartlett about prions Learning, LLC 6–8. Match eachNOT statement FOR at SALE the left OR with DISTRIBUTION its term is false? NOT FOR SALE OR DISTRIBUTION (A–D). A. Prions are infectious proteins. 6. ____ Would be A. Capsid B. Prions have caused disease in the United found in a bacterial B. Prion States. © Joneslysogenic & pathway Bartlett Learning,C. Prophage LLC C. ©Human Jones disease & Bartlett is called Learning,variant CJD. LLC 7. ____ Would be found D. Provirus D. Prions can be transmitted to humans from NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION surrounding ssRNA prion-infected beef. 8. ____ Would be found in an HIV-infected cell © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION STEP B: Application and Analysis 11. Construct a concept map for the Tumor Viruses 24 hours before counting the number of plaques. by using the following terms. Each term should This then got your lab partner thinking. She be used only once. Add arrows and a phrase to says, “If all these bacteriophages are in the sewer, explain the linkage.© Jones & Bartlett Learning, LLC they must have come© fromJones human & Bartlett waste flushed Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION • Adult T-cell leukemia into the sewer. If so, why haven’t the phages • Burkitt’s lymphoma wiped out all the bacteria in the human digestive • Cervical cancer tract?” How would you respond to her • dsDNA question? © Jones• Epstein-Barr & Bartlett virus Learning, (EBV) LLC 15. A person© Jones appears & Bartlett to have died Learning, of rabies. LLCAs a NOT• FORHepatitis SALE B OR DISTRIBUTION coroner,NOT youFOR need SALE to verify OR that DISTRIBUTION the cause of • Hepatitis B virus (HBV) death was rabies. What procedures could you • Hepatitis C use to confirm the rabies virus was the infectious • Hepatitis C virus (HCV) agent? Herpes virus 8 (HV8) 16. As a young genetic engineer with a biotech © Jones & Bartlett• Learning, LLC © Jones & Bartlett Learning, LLC • Human papillomavirus (HPV) company, you have been given a virotherapy NOT FOR SALE• OR Human DISTRIBUTION T-cell lymphotropic virus I (HTLV-1)NOT FOR SALEproject. ORThe DISTRIBUTIONhepatitis B virus is a dsDNA virus • Kaposi sarcoma that during its replicative cycle often produces • ssRNA different forms of virus particles. The ones that 12. Compare the processes of productive infections are filamentous or spherical completely lack a versus latent ©infections. Jones & Bartlett Learning, LLC viral genome and are© thusJones defective; & Bartlett they are Learning, just LLC 13. Illustrate howNOT viruses FOR can causeSALE tumors. OR DISTRIBUTION assembled capsids butNOT with FOR the sameSALE spikes OR as DISTRIBUTION 14. As part of a lab exercise, you and your lab the infective virions. The biotech company wants partner are to estimate the number of you to come up with a plan to use these defective bacteriophages in a sample of sewer water using particles for biotechnology applications. What might you include on your list of applications? © Jonesa plaque & assay Bartlett with E. Learning, coli. You add LLC the phages to © Jones & Bartlett Learning, LLC a lawn of bacteria and let the plates incubate for NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION STEP C: Evaluation and Discussion 17. The Nobel Laureate and British biologist Sir 18. Researchers studying bacterial species that live © Jones & BartlettPeter Learning, Medawar (1915–1987) LLC once remarked © Jones &in Bartlett the oceans Learning, have long beenLLC troubled by the NOT FOR SALEthat OR a virusDISTRIBUTION is “just a piece of bad news wrappedNOT FOR SALEquestion OR of whyDISTRIBUTION these microorganisms have not up in protein.” Explain what he meant by this saturated the oceanic environments. What might statement. be a reason?

9781284240535_CH06_137_168.indd 167 30/12/20 4:56 PM 168 Chapter 6 The Viruses and Other Infectious Agents

19. When discussing the multiplication of viruses, 20. Suppose that all viruses on Earth suddenly © Jones & Bartlett Learning, LLC © Jones &virologists Bartlett preferLearning, to call theLLC process replication, disappeared. How would life on the planet NOT FOR SALErather than OR reproduction. DISTRIBUTION Why do you think NOT FORchange? SALE Would OR life DISTRIBUTION have evolved on Earth if this is so? Would you agree with virologists that viruses had never existed? “replication” is the better term?

9781284240535_CH06_137_168.indd 168 30/12/20 4:56 PM