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Home , Cause (medicine), Disease, Infection, Medical microbiology

Chapter 1: Introduction to Medical is the study of parasites, fungi, , and that are the agents of infectious in . Modern relies on the control of to maintain and quality of . The divisions of medical microbiology include , the study of bacteria that inhabit and/or colonize the and disease; mycology, the study of fungi as causative agents of human disease; , the formal study of the human parasitic (protozoans, helminths, , trematodes and ); and , the study of viruses that cause infectious in humans. Sizes for the considered include the smallest, viruses (50-100nm), bacteria that range from 0.1 µm (Chlamydiae) to 10µm ( rods), fungi ranging from ~8µm (yeasts) up to 10mm in size (filamentous fungi) and metazoan parasites that are visible to the naked eye.

Medical microbiology as a discipline requires a working knowledge of human anatomy and histology, and a comprehension of the associated with the infectious disease process. The human immune response to pathogens is key to the consideration of infectious disease. Understanding the relationship between pathogens and is essential as well. Microbiology places information about pathogenic organisms and their specific characteristics within the context of disease. Developing connections between microbiology and will make more effective in both disciplines.

Special populations are important to consider and should be appreciated for the distinctive infectious disease presentations they reflect. Age-related immuno-compromised status makes the elderly and the very young, especially newborn , particularly at- for respiratory . Health-related can predispose organ transplant recipients, and with disorders, , and to difficult infections. And, unique exposures due to occupation or travel can be a problem for some patient populations. An immunocompromised person is lacking in some aspect of innate or adaptive due to either a primary or secondary immune deficiency. Whatever the route, the net result is that the immunocompromised individual becomes susceptible to with a range of opportunistic pathogens from the commensal microflora and conventional infectious agents that cause a more severe form of disease than in a 'normal' host. This depends on how the patient's condition affects each limb of the , which in turn controls the most likely pathogens. Immunity to infection and sensitivity to normal commensal microbes as pathogens varies throughout life and not just in 'disease' states. Host-Parasite Relationships A parasite is an that makes its living at the expense of another organism, so in a broad sense, all human pathogens fall under the blanket term “parasite”. A parasite derives its nutrients and ecosystem from the host and is able to grow and reproduce in this environment. Medical microbiology presents concepts relating host-parasite relationships and the human immune system’s response to infectious disease. and system imbalance are keys to the understanding of many common . The development of an infection and its eradication frequently involves issues that are defined as much by the host as by the microbial parasite, a balance between host immunity and the of the infectious agent.

NORMAL FLORA The normal microbial flora of the human body is located mainly in the superficial layers and . Gastrointestinal pathogens have some resistance to gastric and bile and agents of infections are resistant to drying. Lower respiratory and upper urogenital tracts are sterile normally, but they are susceptible to microbial “invasion” from adjacent sites. Contamination occurs when microbes come into contact with host surfaces.

Colonization. The skin of a newborn is populated initially by the organisms carried in the urogenital tract of the mother and acquired by the baby at birth. The mother’s skin and breath are additional sources of normal bacteria that become the infant’s commensal population, especially the mucosal normal flora.

The Oral Cavity. Many of the “normal” flora can be disease-causing organisms under the right conditions. are largely responsible for dental caries and pitting of enamel by mutans acidic metabolic by-products is well documented.

Beneficial Effects. Vitamin synthesis and bile degradation are two beneficial effects provided by bacteria to the host (Bacteroides make vitamin K and degrade intestinal bile). Resident microflora inhibit the of growth of potential pathogens, as well as providing mechanical advantages such as suppression of competitor’s adherence, priming of the immune system, maintenance of low redox potential, and bacteriocin secretion (inhibits the growth of bacterial competitors).

NUMBER OF MICROORGANISMS IN COLLECTED SAMPLES

Nasal Washings 106 microbes/ml fluid Saliva 108 microbes/ml Tooth Surfaces 108 microbes/ml Gingival crevices 1011-1012 microbes/ml

PROKARYOTIC cells outnumber EUKARYOTIC cells in the human body, by a factor of 10 to 1!

DISEASE PROGRESSION The period of total infection is from point of first contact until point of complete elimination of the . Overt disease is associated with the onset of symptoms. In a recurrent infection, the disease reappears over with a characteristic rise and fall of agent shedding and symptomatic disease. The seropositive phase occurs where the patient has been exposed to a pathogen and has mounted an response that is reflected in detectable levels of specific immunoglobulin. Incubation is defined as the period from the point of first contact until the point of appearance of symptoms of infection (when “disease is present”). Latent infections remain dormant, and then re-emerge after or a lapse in immune . During the period of communicability the infectious agent is being continuously shed by the patient. To complete the cycle of infection, infectious agents are excreted, and the route of excretion dictates the mechanism of spread. Fecal-oral spread involves excretion within stool samples and may be aided by . Pathogens are often aerosolized in respiratory secretions by sneezing and coughing. STD agents are transmitted by sexual contact with vaginal, cervical or urethral fluids. Zoonotic infections are diverse and cause diseases where humans are either a part of the normal infectious cycle or accidental hosts by contact with vectors or reservoir animals. Some of these agents are excreted in and urine, but also through (widespread presence of the parasite). Examples include bloodstream parasitemia, to ensure uptake by blood-sucking insects (e.g. Anopheles and ) and budding from salivary gland cells to aid viral spread through animal bites.

Pathogen Virulence Mechanisms. Host-parasite interactions can be described as pathogenic vs nonpathogenic (pathogenicity=ability to cause disease or multiply within a host), or invasive as opposed to a successful commensal avirulent status quo (the human as an ). Virulence is a concept of “degree of pathogenicity”. Some viruses and other pathogenic microbes characteristically cause disease and these may express highly specific adhesins or . Virulent organisms cause a specific host that is removed when the encoding a specific or trait is deleted. The controlling the synthesis of these factors are grouped together under the control of a single promoter in pathogenicity islands. Examples of virulence factors include the secreted by tetani (tetanospasmin) and the capsule of that subverts by preventing . Toxin production is a common virulence factor and bacterial can inhibit host cell protein synthesis, stimulate watery secretions, and cause violent symptoms of disease in the host. Attachment and adherence via specific epithelial and mucosal receptors (integrins) is another form of virulence because adhesion protects pathogens from the of mucosal surfaces. Vibrio binds to sites on the villi of the jejunum or ileum. Virulence is mediated by strength of attachment phenomena. Specifically pathogenic strains of have capsular (K1) that make the bacteria neurotrophic; most strains of E. coli are harmless commensal organisms that occupy space in the human gastrointestinal system.

Inhibition of host immune mediators. Inhibiting host immune cell products to blunt the anti-microbial response is a strategy of many pathogens. Some organisms produce leukocidins that kill and macrophages. Others have intracellular growth patterns that allow them to avoid detection by the host’s immune system (these will be discussed with the pathogen groups). and degrade human C5a using a peptidase . IgA protease is an immunoglobulin-destroying enzyme produced by Streptococcus pneumoniae, Neisseria meningitidis and . Complement compoenent C3b binding is inhibited by HSV envelope glycoprotein and vaccinia virus accelerates the decay of complement C3 convertase. aureus produces and this enzyme breaks down in phagolysosomes to limit bactericidal activity. Each of these mechanisms is a unique process for pathogen survival.

Molecular mimicry. Another pathogen survival mechanism is to change its surface composition, utilizing a mask to avoid immune detection. One way to do this is simply to become coated with human “self-antigens”. This method is used by (coats itself with fibronectin); Neisseria meningitidis (coats itself with circulating host IgA); and vaccinia virus (incorporates host sialic acid into its capsular ). Presenting a changing target is the strategy for Trypanosomes and virus (gene switching changes surface proteins). Koch’s postulates are an important set of criteria that can be used to judge whether a microbe is the cause of a disease in question. First, the organism must occur in every case of the disease, and must be responsible for the pathological changes observed. Next, the organism must cause the same disease in a new host exposed to an isolate, and must in turn be isolated from the new host.

Epidemiology is the study of disease patterns and trends, of the occurrence, distribution and control of disease in populations. It also deals with disease tracking and prevention. Disease is the movement of the infectious agent from one host to another. The risk of infection is dependent not just upon an individual patient's susceptibility, but on the level of disease within the population, the extent of population mixing and “”, added to the specific features of disease spread, such as communicable period, route and ease of transmission (infectiousness).

Modes of Transmission. Numerous modes of transmission contribute to the spread of human disease. For an infectious agent to persist within a population a cycle of transmission must be established leading from a contaminated source to a susceptible host and further propagating through the population.

Composite diagram illustrating the various modes and routes of disease transmission.

Direct infection is the movement of a pathogen from human to human. Examples of organisms causing direct infection are typhi and Shigella species, both of which infect humans only. Indirect transmission involves human to soil, water or surface dissemination of pathogens and infection of another human through contact with contaminated materials. This idea encompasses vehicle-borne transmission, whether through infected everyday objects or surgical instruments. Vibrio cholera is an example of a pathogen that is transmitted through contaminated water, especially in brakish coastal waters. Zoonotic transmission occurs through exposure to a nonhuman animal source of infection. The -borne agents like Borrelia and Rickettsia are included here as well as Spirillum, Brucella and , that are contracted through animal bites or contact with animal products. Elimination is a potential outcome for a healthy host, whereby the parasite is eradicated at the end of infection cycle.

Routes of Transmission. The direct route means physical contact between humans or between a human and an animal to cause disease. Portals of entry include the gastrointestinal tract, respiratory mucosa, genital mucosa, and direct through the skin. Mucous membranes are especially important (STDs are transmitted in this way). The airborne route or respiratory droplet transmission is very important for viral pathogens and infections (aerosols). are inanimate objects contaminated with microorganisms, like drinking cups, towels and computer keyboards. The waterborne route is an especially important for enteric disease and it’s an important route for fecal-oral transmission (ingestion). - borne transmission is critical for some viral () & zoonotic infections (arthropod borne parasites).

MORBIDITY/MORTALITY Morbidity is the number of cases (or the ) of a specific disease per unit population (cases per 100,000). Mortality is the number of due to a specific disease per unit population (deaths per 100,000). The “Centers for Disease Control and Prevention” publishes the Morbidity and Mortality Weekly Report (MMWR), a monthly journal that documents important disease trends in the United States. http://www.cdc.gov/mmwr/

EUROPEAN BUBONIC STATISTICS

Year 1348 67% 100% 1361 50% 90% 1371 10% 50% 1382 5% 50% 1663-1668 last European 1890 San Francisco 1903 Sydney, Australia Rates of morbidity and mortality; and incidence. To illustrate morbidity/mortality concepts, for the U.S., has a low morbidity and low mortality, because it is present at very low incidence (the disease is not , ie, not a typical pathogen for the region). Where Chagas’ disease is present, it results in low mortality because the disease has a chronic nature, and is not an outcome. In contrast, viral influenza has a high morbidity and relatively low mortality; many people are infected every year, but a low percentage of those affected will die from the disease. virus on the other hand has a low morbidity and a high mortality in the U.S.; it is hardly found, but is nearly always lethal. Prevalence is defined as “the number of cases of infection per unit of population at a single point in time”. Disease incidence refers to “the number of new cases of infection per unit of population over a specified period of time”. Disease levels vary throughout the year for some types of infection (for example the rise in respiratory tract infections during the winter months) with others remaining at a steady state (like ). Some infections have periodic cycles measured over longer scale, for example a four-year cycle for Mycoplasma . Patterns of infectious diseases vary throughout the world, depending upon factors such as environment, weather, economic factors, , behavior and the local healthcare systems. It is essential that every clinician is aware of regional disease patterns for effective diagnosis, treatment and control of infection within their own practice of medicine. For serious communicable diseases in the US, a part of surveillance is the legal requirement for medical personnel to inform the local health department of every diagnosis of a notifiable disease.

Epidemiological data can be presented as age-related incidence (see , below); geographical representation (); social group affiliation and distribution over time (AIDS). Diphtheria is the first component of the DPT (Diphtheria, Pertussis, ). For people 55 and older, there is an increase in morbidity because the DPT vaccine was unavailable 50 years ago, and data represented by age group shows that almost everyone had the disease at one time. For the example of morbidity and geographical variance, syphilis is especially high in the rural, southern part of the US, while its incidence is lower nationally. This is in part due to historical problems with healthcare access in rural areas with high minority populations (socioeconomic factors).

Finally, AIDS is a unique example of epidemiology in many respects. Initially thought to be a disease of specific population segments (Haitians, hemophiliacs, heroin addicts, homosexuals), it is now recognized to have more complexity (social group demographic). It is also a group of diseases that reflect primary underlying immunodeficiency, and this is a recurring theme throughout the study of infectious disease. And finally, the appearance of AIDS is changing over time, with increases in the incidence among the female and pediatric populations in the US, as well as in the MSM population (the CDC definition of “men who have sex with men” encompasses the highest-risk homosexual and bisexual male population).

The changing US mortality rates for HIV infection over time in the population, compared with other leading causes of death in this population.

DISEASE DEFINITIONS A cluster of cases in a specific area or a single household is termed an outbreak, and is usually related to a local exposure source. An increase in case incidence over a larger region, perhaps an entire state or country, is described as an . This is less likely to be caused by a single source, and a concerted effort might be required to control the spread. An increase in incidence over a much larger area, several countries or a hemisphere, is described as a pandemic. Effective control of outbreaks requires prompt diagnosis, descriptive epidemiology [source(s) of infection, mode/route of transmission, identification of additional people at risk] and the rapid use of an effective way to abort the infection cycle.

CDC EMERGING INFECTIONS PRIORITY ISSUES, 1999-2004 • • Opportunistic infections • Food and water safety • Vectors and animal health • Blood safety • Infections that cause chronic diseases • Vaccine development (malaria; ; influenza virus) • Maternal and child health • Health of travelers and refugees

PATHOGEN – DISEASE PAIRS

Staphylococcus aureus – staphylococcal toxic shock Streptococcus pyogenes – Strep Streptococcus pneumoniae – media and pneumococcal pneumonia Neiserria gonorrhoeae – sexually transmitted infection Neiserria meningitidis - Legionella pneumophila – Legionairre’s disease Bordetella pertussis – diphtheria - Diphtheria – Gas - Tetanus Salmonella typhimurium - Shigella dysenteriae – - Cholera Yersinia pestis – Treponema pallidum - Syphilis Propionibacterium acnes - Acne

REFERENCES: Centers for Disease Control and Prevention, http://www.cdc.gov/, information accessed 11-10-2004. Merck Manual of Diagnosis and , “The Biology of Infectious Diseases”. (1999) 17th Edition, Merck Res. Labs, Whitehouse Station, NJ, pp 1088-1097. Murray, PR, Rosenthal, KS, Kobayashi, GS, and Pfaller, MA (2002) Medical Microbiology, 4th Edition, Mosby, Inc., St. Louis, MO pg 1-24; 78-81; 175-184.