CChapterhapter Pathogenesis of 2

2.1 Stages of infectious 21 Encounter with 2.2 Pathogenicity 23 The initial contact with a given microbial species is Self-assessment: questions 26 critically important. The indigenous microbial fl ora Self-assessment: answers 27 is already present on the body surface. acquired from this pool of organisms are said to be ‘endogenous’, e.g. urinary tract infection. Organisms Overview acquired as a result of transmission from an external Given the ubiquitous nature of microorganisms and the source are said to be exogenous. The major routes of many occasions on which they come into contact with transmission are: humans, it is surprising how infrequently infectious occur. The reason why some organisms can • direct contact (including intimate sexual peacefully coexist with humans while others go on to contact), e.g. soft tissue infections, gonorrhoea, produce disease lies in the nature of the interaction genital herpes between microbe and host. Much has been learnt in • inhalation/droplet infection, e.g. common cold, recent years about mechanisms of microbial disease, pneumonia especially at the molecular and cellular levels. There is • ingestion/faecal–oral route, e.g. gastroenteritis a growing awareness of the active contribution of the • inoculation or trauma, e.g. tetanus, malaria environmental context of infection. Knowledge of these processes is necessary to understand how to diag- • transplacentally, e.g. congenital toxoplasmosis. nose, treat and prevent infection effectively. Colonisation The initial encounter with a new microbial species 2.1 Stages of infectious disease may result in nothing more than short-lived contact with an external body surface. The micro- organism needs to survive and multiply under Learning objectives local conditions (e.g. of temperature and pH) to You should: establish itself in its new habitat. It must success- • know the mechanisms that microorganisms use to fully compete against an established indigenous infection microbial fl ora and resist local defence mechanisms. • understand infection as a staged biological Some species are capable of producing mucolytic process enzymes to help them penetrate the layer of mucus coating internal body surfaces. Other species have specifi c adhesins that enable binding with The process through which microorganisms cause receptor sites on human cells (e.g. gonococcal disease involves several or all of the following pili attachment to urethral epithelium and infl uenza stages: virus adherence to glycoprotein receptors on upper respiratory mucosal cells). Locally active IgA 1. encounter produced by some mucosal surfaces can be inacti- 2. colonisation vated by bacteria such as Haemophilus infl uenzae, 3. penetration Streptococcus pneumoniae and Neisseria meningitidis, 4. spread which produce IgA protease. Once established 5. damage on a body surface, an organism is said to have 6. resolution. colonised that site. However, not all organisms 21

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that colonise will go on to invade and damage tissues, along tissue planes or via the veins and underlying host tissues. lymphatic vessels. The vascular route of spread is a particularly effective means of delivering organisms Penetration of anatomical barriers from an initial focus to distant sites around the body. In order to invade living human tissues, a micro- Organisms may play an active part in spread by organism must breach surface barriers. In the case of destroying cells, or even by self-propulsion. As the the skin, bacteria probably do not penetrate intact organisms spread, evasion of host defences becomes surfaces. Infection thus requires a break in the epi- increasingly important. thelial cover due to trauma, surgical wounds, chronic skin disease or insect bites. Some parasites (e.g. Mechanisms of damage schistosomes, the cause of bilharzia) can penetrate Microorganisms damage tissues by a variety of intact skin. The respiratory tract is continuously mechanisms: exposed to air-borne organisms. However, the upper respiratory tract functions as an inertial fi ltration • bulk effect system and protects the more delicate lungs from • toxin mediated exposure to inhaled particles. The cough refl ex and • altered function of host systems the mucociliary escalator provide back-up, expelling • host response to infection. any particles inhaled into the airways. Infective par- ticles (e.g. droplet nuclei, less than 5 μm in diameter) Bulk effect may reach the alveoli and establish infection. In the The sheer bulk of organisms may obstruct a gastrointestinal tract, some disease-causing organ- hollow organ, e.g. some helminth infections of the isms damage the mucosal surface by releasing intestine. Swelling of infected tissues can cause cytotoxins (e.g. those causing dysentery), while pressure on adjacent hollow organs or neurovascu- others (Salmonella typhi) are taken up by the M cells lar bundles. overlying gut-associated lymphoid tissue in Peyer’s patches. The fetus is not normally exposed to micro- Toxins organisms in utero. Only a small group of organisms Toxin-mediated disease may also be caused by pro- cause infection in the mother during pregnancy and duction of microbial substances that damage cells. can also traverse the placenta to cause intrauterine Most bacterial toxins (Table 1) are proteins released infections such as toxoplasmosis, rubella, syphilis by the organism or a lipopolysaccharide complex and cytomegalovirus infection. If an organism is located in the cell wall and liberated during cell capable of intracellular infection (e.g. tuberculosis, growth or lysis. A number of specifi c toxins have chlamydial disease or viral infection), it must also be been shown to play an essential role in correspond- capable of cell penetration and survival in an intra- ing diseases. They include: cellular habitat. At this stage, evasion or subversion of host defences becomes important to microbial • tetanospasmin: tetanus survival. • botulinum toxin: botulism • cholera toxin: cholera Spread • diphtheria toxin: diphtheria. An invading may spread by one or In these infections, the toxin causes the main features more routes: direct extension through surrounding of the disease. However, toxins do not have to

Table 1 Some examples of bacterial toxins

Species Toxin Type Gene location

Clostridium botulinum Botulinum toxin Neurotoxin Bacteriophage Clostridium tetani Tetanospasmin Neurotoxin Plasmid Corynebacterium diphtheriae Diphtheria toxin A-B ADP ribosylating Bacteriophage Escherichia coli Heat-labile toxin A-B ADP ribosylating Plasmid Vibrio cholerae Cholera toxin A-B ADP ribosylating Chromosome

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2 2 : 3 2 : 0 23 1

Two 6 0 0 2 / 6 / 2 112/6/2006 10:23:22 AM c to ciency virus Pathogenicity c and immune defences. c and immune c preferences for certain host ed mechanism constitute a regulon. cation of the structural and controller genes cation of the structural The genetic determinants of microbial pathoge- determinants The genetic Pathogenesis of viral infection As obligate intracellular parasites, viruses require effective mechanisms of transmission, adherence and cellular penetration to establish infection. Many viruses have specifi tissues (e.g. rhinoviruses for the upper respiratory epithelium and human immunodefi (HIV) for CD4 T lymphocytes). Viruses can spread by lysis of the primary infected cell and secondary viraemia, or by formation of bridges (syncytia) between cells. Human cells need not be destroyed. Viral penetration of the host cell cytoplasmic mem- brane without cell rupture is a complex process in which the virus may use cell surface molecules to subvert normal membrane and cytoskeletal func- tions. Viruses can be continually formed at the cell surface or the genome can even be integrated into Some organisms change their surface antigenic antigenic surface their change organisms Some immune evade the host intermittently to makeup trypanosomes). borrelias and system (e.g. for the genes coding complex. In bacteria, nicity are on the the chromosome, may be on toxin production DNA) or even in a bac- plasmids (extrachromosomal of ‘virulence factors’ in most teriophage. Expression to an environmental trigger. cases is a response animals resulted in the devel- Work with laboratory gene trap for the study of opment of a promoter The system, known as in bacterial pathogenesis. technology (IVET), led to the vitro expression identifi disease. The products responsible for promoting genes have been placed in of the disease-promoting and toxins, and six categories: adhesins, invasins factors. The cloaking, shielding and scavenging to environ- genetic switching on and off in response to survive mental triggers allows the bacterium mechanical, non-specifi sigma factors Post-transcriptional regulation via the microbial provides a molecular link between response genome and the organism’s physiological groups of pro- to its immediate environment. Whole as the microbe teins can be up- or downregulated under the control adapts to its environment. Proteins of a single, unifi are specifi Many aspects of bacterial physiology dependent on a particular phase of growth. If also to be subject to microbial density, they are said a group of low- quorum sensing, a process in which as acyl homo- molecular-weight compounds known in a simple serine lactones (AHLs) are expressed system of intercellular communication. ). c- , and amma- brous nodules brous S. pneumonia Mycobacterium tuberculosis Pathogenicity

3 tissue damage and the factors that might limit this tissue damage and the factors that might damage microorganism, the human recipient and the intervening environment in determining the outcome of an infection. 2

to infection-related know the principal contributors understand the balance between the d Learning objectives You should: • • d antiphagocytic toxins such as staphylococcal leuko- cidin) and some have a capacity to survive inside macrophages (such as Individual species or strains vary in their ability to cause disease. A prerequisite of microorganism- induced damage is microbial growth. Microorgan- isms have a great variety of strategies to enable continued growth in a hostile environment. They compete for substrates such as iron (an important growth-limiting factor) and other trace elements. Many species have defences against phagocytic cells (e.g. the polysaccharide capsule of 2.2 The host response usually begins with an infl The host response usually begins with The host response to infection humoral or cell- tory reaction, and is followed by a cause damage mediated immune response. This may of tissues, forma- due to swelling, increased fragility intracellu- tion of pus, scarring or . Chronic fi lar infection may cause formation of infection can and a state of latency from which acute be re-established at a much later stage. Altered function of organs, Altered function tissues or cells can change the function of organs, Microbial invasion changes can be the result of tissues or cells. These acting to remove the physiological mechanisms increased bowel motility leading infective agent, e.g. and sneezing. to diarrhoea, or coughing destroy cells to cause damage. They can cause sub- They can damage. to cause cells destroy to function, adding or alter cellular lethal damage exo- subtle ways. Many process in more the disease and B A (active) two principal subunits: toxins have specifi tissue The B subunit determines (binding). after cellular damage the A subunit causes ity, while subunit and subsequent penetra- binding by the B tion of the cell membrane. n i . 9 8 2 0 1 F - 2 0 0 h CCh002-F10289.indd 23 Two: Pathogenesis of infection

the host cell’s own genome. The long-term survival immune systems are depressed by drugs or infec- of viruses within human cells as obligate intracellu- tion, particularly by HIV. lar parasites places them beyond the reach of immune defences. Some viruses integrate into the host cell Infection and the environment genome to produce a latent state. Viral damage is caused by the cytotoxic effects of the virus or by The model mechanism of infection that we inherited host immune attack. Mechanisms of late-stage viral from Robert Koch places its emphasis on an identifi - damage include autoimmune, immune-complex or able microbial pathogen; the presumed external neoplastic disease. agent of disease. This emphasis may have been Pathogenesis of fungal infection useful in the early days of the germ theory of disease. However, a preoccupation with the microorganism Fungal disease, particularly its life-threatening to the exclusion of all other factors misses the wider extreme, is relatively rare despite the many species context of the discoveries made by the early pioneers of fungi present in the environment and on the of microbial disease research. Koch provided a rule human body surface. Most fungal infections appear of thumb to establish the role of a given microorgan- to require a breach in host defences in order to ism as the causal agent of a given disease. Unfortu- become established. Yeasts often cause mucosal nately, Koch’s postulates, as they are known, are infl ammation following alteration of either vaginal only rarely fulfi lled, despite attempts to bring them or gastrointestinal fl ora. Dermatophytic fungi cause up to date with a molecular biological slant. a variety of skin conditions but rarely cause more The early immunologists recognised the funda- invasive disease in immunocompetent patients mental importance of the infected person’s response because they are restricted to the skin. There is no in the development of infectious disease. Accepting good evidence for the involvement of toxins in the contribution of humoral and cellular immunity, fungal disease. Most damage is probably caused by tissue reaction and immune compromise to the the host response. course of an infection leads to a more sophisticated model of infection as an interactive process between Pathogenesis of parasitic infections human and microbe with destructive consequences. Protozoal and helminth infections have a complex Until very recently, the environment in which the pathogenesis, which is best understood by referring initial interaction between microbe and host occurs to the parasite’s life cycle. Some protozoal and hel- was seen as little more than a passive backdrop to minth infections require transmission by a disease infection, with the possible exception of some vector- vector. The vector is often an arthropod. The devel- borne parasitic infections. The critical role of the opment of disease depends on a three-way relation- environment in mediating the encounter with a ship between microorganism, vector and human potentially infective microorganism, and thereby victim in these infections. The ecology of the vector infl uencing the outcome, is a more recent idea. (sometimes known as the ‘intermediate host’) is The emerging picture of infectious disease patho- critical to the long-term survival of the parasite genesis is one in which the outcome is determined within a human population. In developed countries, by a three-way tussle between microorganism, parasitic infections are most common in interna- human recipient and the intervening environment. tional travellers, the sexually active, immunocom- The complex cellular and molecular events that promised patients and poor people. The application determine the fi nal outcome of each encounter are of novel molecular parasitology techniques has pro- likely to throw more light on the origins of disease. vided new insights into the mechanisms of parasite This multilayered picture of infection as a process disease. encompassing molecular events, cellular events, tissue, whole organism, habitat and geography is Opportunist infections known as ‘biocomplexity’. If an organism is capable of causing disease in an apparently healthy individual, it is clearly aggres- Dynamic biological processes sively pathogenic. If it is normally incapable of causing disease but can do so only when the human The dynamics of the interaction between micro- body is compromised in some way, it is said to be organism and human cells are beginning to open up opportunist. Opportunist infections are of particular to mechanistic analysis. The application of mathe- importance in hospital patients and in people whose matical modelling to theoretical biology now allows 24

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us to predict the consequences of introducing a new encounter between two populations attempting to disease-causing microbe to a human population. The restore biological order—a noisy negotiation for a perturbations from the initial steady-state popula- peaceful settlement. This newer way of looking at tions of microorganisms and humans resemble a pathogenesis (the origins of disease) complements discordant state that demands resolution before mainstream germ theory, and has taken our harmony can be restored. Infection can be thought understanding of infectious disease processes into of as the unsought consequence of an accidental unfamiliar multidisciplinary territory. Two

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Extended matching questions Any one answer can be used once, more than once or not at all. The following is a list of questions: A. Cholera 1. What is an example of a vertical B. Gonorrhoea infection? C. Pneumonia 2. What is the best example of an infection that D. Staphylococcal skin infection requires initial colonisation of a body surface? E. Fetal (intrauterine) rubella 3. Which infection listed is most likely to result F. Viral gastroenteritis from inhalation? 4. Which one of these infections is most often Short notes questions transmitted in air? 5. Which infection needs an initial breach in the Write short notes on the following: body surface? 1. How microorganisms cause damage in human 6. In which infection does a leukocidin play a disease role? 2. A comparison of pathogenesis of bacterial and 7. Which infection is caused by an obligate viral infections intracellular organism? 3. The main routes for transmission of infectious 8. Which infection is entirely due to the action of diseases and how microorganisms penetrate a toxin? the respective anatomical barriers 9. In which infection is droplet size a critical factor? Viva questions 10. Which infection does not require microbial penetration of the body surface? 1. What is the difference between colonisation and infection? Select the single answer from the list below that best 2. Can microorganisms be divided into pathogens matches each one of the questions in the list above. and non-pathogens?

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Extended matching answers 7. F: All viruses are obligate intracellular parasites. A few 1. F: bacteria are obligate intracellular organisms, e.g. Fetal rubella is transmitted from the mother to the chlamydias, and a larger number are facultative fetus in utero and is therefore an example of a intracellular organisms (e.g. Legionella, Listeria and vertical infection. All others listed are exogenous Salmonella). The vibrio that causes cholera is extra- infections due to external agents, with the possible cellular and staphylococci can be both intra- and exception of some staphylococcal skin infections, extracellular. which can be caused by inoculation of bacteria from the endogenous skin fl ora. 8. A: The profuse diarrhoea seen in patients with cholera 2. B: is almost entirely due to the extracellular action of Gonorrhoea requires initial colonisation of the ure- cholera toxin. thral mucosa and adhesion to the epithelial surface via pili. Cholera and viral gastroenteritis require 9. C: ingestion, pneumonia requires inhalation and sta- Inhaled droplet size is of critical importance in the phylococcal skin infection can result from direct pathogenesis of pneumonia, where droplets must inoculation. be of the right diameter to reach the smaller air spaces where the bacteria or viruses that they 3. C: contain can establish infection. Particle size is of Pneumonia is usually caused by bacteria or lesser or no importance in all the other infections viruses that have been inhaled into the smaller listed. airways. 10. A: 4. C: Cholera is due to the effect of a toxin that acts on the intestinal mucosal surface and therefore Pneumonia is transmitted by inhalation of does not require penetration of intestinal epithelial infective droplet nuclei. Gonorrhoea requires inti- cells. Intrauterine rubella requires entry of the mate body contact. Cholera requires a major break- virus, fi rst into the mother’s circulation, and then down in sewage disposal and other hygiene failures. into the fetal bloodstream. The other listed infec- Viral gastroenteritis is transmitted by the faecal–oral tions all depend on penetration of an epithelial route, involves unwashed hands and may some- surface. times be spread via the air to those in close proximity. Short notes answers 5. D: Staphylococcal skin infection usually requires at 1. The main topic areas of bulk effect, least a microscopic breach in the skin surface. Pneu- altered function, toxin-mediated effects and monia results from inhalation. Gastroenteritis and host response should be covered, with cholera result from ingestion, and intrauterine infec- examples. tion results from transplacental spread. 2. Could be tackled as a table. Follow the sequence of acquisition, colonisation, 6. D: penetration, spread and damage. Leukocidin plays a part in the invasion stage of Give examples of bacteria and some of the more severe staphylococcal skin viruses. infections. It is not a feature of pneumonia, 3. Follow principal routes of transmission and cholera, viral gastroenteritis or intrauterine means of penetration; probably best done infection. using a system-based approach. 27

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Viva answers patient. Refer to the balance between patient and microbe and its modifi cation 1. Briefl y defi ne the two terms, then give specifi c by host defences, antibiotics and examples and discuss how confusion of the two environmental factors. Give specifi c examples terms can cause problems in clinical practice. of how concepts of pathogenesis have 2. Some microbes have not yet been shown to changed recently through developments in cause human infection. Mention the spectrum molecular and cell biology and now challenge of virulence from opportunist to those that a simplistic pathogen–non-pathogen can be highly lethal in the previously healthy dichotomy.

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