Download Pathogenesis of infection and more Lecture notes Infectious disease in PDF only on Docsity!
Pathogenesis of infection
2.1 Stages of infectious disease 21 2.2 Pathogenicity 23 Self-assessment: questions 26 Self-assessment: answers 27
ChapterChapter
Encounter with microorganisms
The initial contact with a given microbial species is critically important. The indigenous microbial flora is already present on the body surface. Infections acquired from this pool of organisms are said to be ‘endogenous’, e.g. urinary tract infection. Organisms acquired as a result of transmission from an external source are said to be exogenous. The major routes of transmission are:
- direct contact (including intimate sexual contact), e.g. soft tissue infections, gonorrhoea, genital herpes
- inhalation/droplet infection, e.g. common cold, pneumonia
- ingestion/faecal–oral route, e.g. gastroenteritis
- inoculation or trauma, e.g. tetanus, malaria
- transplacentally, e.g. congenital toxoplasmosis.
Colonisation
The initial encounter with a new microbial species may result in nothing more than short-lived contact with an external body surface. The micro- organism needs to survive and multiply under local conditions (e.g. of temperature and pH) to establish itself in its new habitat. It must success- fully compete against an established indigenous microbial flora and resist local defence mechanisms. Some species are capable of producing mucolytic enzymes to help them penetrate the layer of mucus coating internal body surfaces. Other species have specific adhesins that enable binding with receptor sites on human cells (e.g. gonococcal pili attachment to urethral epithelium and influenza virus adherence to glycoprotein receptors on upper respiratory mucosal cells). Locally active IgA produced by some mucosal surfaces can be inacti- vated by bacteria such as Haemophilus influenzae , Streptococcus pneumoniae and Neisseria meningitidis , which produce IgA protease. Once established on a body surface, an organism is said to have colonised that site. However, not all organisms
Overview Given the ubiquitous nature of microorganisms and the many occasions on which they come into contact with humans, it is surprising how infrequently infectious diseases occur. The reason why some organisms can peacefully coexist with humans while others go on to produce disease lies in the nature of the interaction between microbe and host. Much has been learnt in recent years about mechanisms of microbial disease, especially at the molecular and cellular levels. There is a growing awareness of the active contribution of the environmental context of infection. Knowledge of these processes is necessary to understand how to diag- nose, treat and prevent infection effectively.
2.1 Stages of infectious disease
Learning objectives You should:
- know the mechanisms that microorganisms use to cause infection
- understand infection as a staged biological process
The process through which microorganisms cause disease involves several or all of the following stages:
1. encounter 2. colonisation 3. penetration 4. spread 5. damage 6. resolution.
that colonise will go on to invade and damage underlying host tissues.
Penetration of anatomical barriers
In order to invade living human tissues, a micro- organism must breach surface barriers. In the case of the skin, bacteria probably do not penetrate intact surfaces. Infection thus requires a break in the epi- thelial cover due to trauma, surgical wounds, chronic skin disease or insect bites. Some parasites (e.g. schistosomes, the cause of bilharzia) can penetrate intact skin. The respiratory tract is continuously exposed to air-borne organisms. However, the upper respiratory tract functions as an inertial filtration system and protects the more delicate lungs from exposure to inhaled particles. The cough reflex and the mucociliary escalator provide back-up, expelling any particles inhaled into the airways. Infective par- ticles (e.g. droplet nuclei, less than 5 μm in diameter) may reach the alveoli and establish infection. In the gastrointestinal tract, some disease-causing organ- isms damage the mucosal surface by releasing cytotoxins (e.g. those causing dysentery), while others ( Salmonella typhi ) are taken up by the M cells overlying gut-associated lymphoid tissue in Peyer’s patches. The fetus is not normally exposed to micro- organisms in utero. Only a small group of organisms cause infection in the mother during pregnancy and can also traverse the placenta to cause intrauterine infections such as toxoplasmosis, rubella, syphilis and cytomegalovirus infection. If an organism is capable of intracellular infection (e.g. tuberculosis, chlamydial disease or viral infection), it must also be capable of cell penetration and survival in an intra- cellular habitat. At this stage, evasion or subversion of host defences becomes important to microbial survival.
Spread
An invading microorganism may spread by one or more routes: direct extension through surrounding
tissues, along tissue planes or via the veins and lymphatic vessels. The vascular route of spread is a particularly effective means of delivering organisms from an initial focus to distant sites around the body. Organisms may play an active part in spread by destroying cells, or even by self-propulsion. As the organisms spread, evasion of host defences becomes increasingly important.
Mechanisms of damage
Microorganisms damage tissues by a variety of mechanisms:
- bulk effect
- toxin mediated
- altered function of host systems
- host response to infection.
Bulk effect
The sheer bulk of organisms may obstruct a hollow organ, e.g. some helminth infections of the intestine. Swelling of infected tissues can cause pressure on adjacent hollow organs or neurovascu- lar bundles.
Toxins
Toxin-mediated disease may also be caused by pro- duction of microbial substances that damage cells. Most bacterial toxins (Table 1) are proteins released by the organism or a lipopolysaccharide complex located in the cell wall and liberated during cell growth or lysis. A number of specific toxins have been shown to play an essential role in correspond- ing diseases. They include:
- tetanospasmin: tetanus
- botulinum toxin: botulism
- cholera toxin: cholera
- diphtheria toxin: diphtheria. In these infections, the toxin causes the main features 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
Two: Pathogenesis of infection
the host cell’s own genome. The long-term survival of viruses within human cells as obligate intracellu- lar parasites places them beyond the reach of immune defences. Some viruses integrate into the host cell genome to produce a latent state. Viral damage is caused by the cytotoxic effects of the virus or by host immune attack. Mechanisms of late-stage viral damage include autoimmune, immune-complex or neoplastic disease.
Pathogenesis of fungal infection
Fungal disease, particularly its life-threatening extreme, is relatively rare despite the many species of fungi present in the environment and on the human body surface. Most fungal infections appear to require a breach in host defences in order to become established. Yeasts often cause mucosal inflammation following alteration of either vaginal or gastrointestinal flora. Dermatophytic fungi cause a variety of skin conditions but rarely cause more invasive disease in immunocompetent patients because they are restricted to the skin. There is no good evidence for the involvement of toxins in fungal disease. Most damage is probably caused by the host response.
Pathogenesis of parasitic infections
Protozoal and helminth infections have a complex pathogenesis, which is best understood by referring to the parasite’s life cycle. Some protozoal and hel- minth infections require transmission by a disease vector. The vector is often an arthropod. The devel- opment of disease depends on a three-way relation- ship between microorganism, vector and human victim in these infections. The ecology of the vector (sometimes known as the ‘intermediate host’) is critical to the long-term survival of the parasite within a human population. In developed countries, parasitic infections are most common in interna- tional travellers, the sexually active, immunocom- promised patients and poor people. The application of novel molecular parasitology techniques has pro- vided new insights into the mechanisms of parasite disease.
Opportunist infections
If an organism is capable of causing disease in an apparently healthy individual, it is clearly aggres- sively pathogenic. If it is normally incapable of causing disease but can do so only when the human body is compromised in some way, it is said to be opportunist. Opportunist infections are of particular importance in hospital patients and in people whose
immune systems are depressed by drugs or infec- tion, particularly by HIV.
Infection and the environment
The model mechanism of infection that we inherited from Robert Koch places its emphasis on an identifi- able microbial pathogen; the presumed external agent of disease. This emphasis may have been useful in the early days of the germ theory of disease. However, a preoccupation with the microorganism to the exclusion of all other factors misses the wider context of the discoveries made by the early pioneers of microbial disease research. Koch provided a rule of thumb to establish the role of a given microorgan- ism as the causal agent of a given disease. Unfortu- nately, Koch’s postulates, as they are known, are only rarely fulfilled, despite attempts to bring them up to date with a molecular biological slant. The early immunologists recognised the funda- mental importance of the infected person’s response in the development of infectious disease. Accepting the contribution of humoral and cellular immunity, tissue reaction and immune compromise to the course of an infection leads to a more sophisticated model of infection as an interactive process between human and microbe with destructive consequences. Until very recently, the environment in which the initial interaction between microbe and host occurs was seen as little more than a passive backdrop to infection, with the possible exception of some vector- borne parasitic infections. The critical role of the environment in mediating the encounter with a potentially infective microorganism, and thereby influencing the outcome, is a more recent idea. The emerging picture of infectious disease patho- genesis is one in which the outcome is determined by a three-way tussle between microorganism, human recipient and the intervening environment. The complex cellular and molecular events that determine the final outcome of each encounter are likely to throw more light on the origins of disease. This multilayered picture of infection as a process encompassing molecular events, cellular events, tissue, whole organism, habitat and geography is known as ‘biocomplexity’.
Dynamic biological processes
The dynamics of the interaction between micro- organism and human cells are beginning to open up to mechanistic analysis. The application of mathe- matical modelling to theoretical biology now allows
Two: Pathogenesis of infection
us to predict the consequences of introducing a new disease-causing microbe to a human population. The perturbations from the initial steady-state popula- tions of microorganisms and humans resemble a discordant state that demands resolution before harmony can be restored. Infection can be thought of as the unsought consequence of an accidental
encounter between two populations attempting to restore biological order—a noisy negotiation for a peaceful settlement. This newer way of looking at pathogenesis (the origins of disease) complements mainstream germ theory, and has taken our understanding of infectious disease processes into unfamiliar multidisciplinary territory.
Pathogenicity
Two
Extended matching answers
- F:
Fetal rubella is transmitted from the mother to the fetus in utero and is therefore an example of a vertical infection. All others listed are exogenous infections due to external agents, with the possible exception of some staphylococcal skin infections, which can be caused by inoculation of bacteria from the endogenous skin flora.
2. B:
Gonorrhoea requires initial colonisation of the ure- thral mucosa and adhesion to the epithelial surface via pili. Cholera and viral gastroenteritis require ingestion, pneumonia requires inhalation and sta- phylococcal skin infection can result from direct inoculation.
3. C:
Pneumonia is usually caused by bacteria or viruses that have been inhaled into the smaller airways.
4. C:
Pneumonia is transmitted by inhalation of infective droplet nuclei. Gonorrhoea requires inti- mate body contact. Cholera requires a major break- down in sewage disposal and other hygiene failures. Viral gastroenteritis is transmitted by the faecal–oral route, involves unwashed hands and may some- times be spread via the air to those in close proximity.
5. D:
Staphylococcal skin infection usually requires at least a microscopic breach in the skin surface. Pneu- monia results from inhalation. Gastroenteritis and cholera result from ingestion, and intrauterine infec- tion results from transplacental spread.
6. D:
Leukocidin plays a part in the invasion stage of some of the more severe staphylococcal skin infections. It is not a feature of pneumonia, cholera, viral gastroenteritis or intrauterine infection.
7. F:
All viruses are obligate intracellular parasites. A few bacteria are obligate intracellular organisms, e.g. chlamydias, and a larger number are facultative intracellular organisms (e.g. Legionella , Listeria and Salmonella ). The vibrio that causes cholera is extra- cellular and staphylococci can be both intra- and extracellular.
- A : The profuse diarrhoea seen in patients with cholera is almost entirely due to the extracellular action of cholera toxin.
- C: Inhaled droplet size is of critical importance in the pathogenesis of pneumonia, where droplets must be of the right diameter to reach the smaller air spaces where the bacteria or viruses that they contain can establish infection. Particle size is of lesser or no importance in all the other infections listed.
- A: Cholera is due to the effect of a toxin that acts on the intestinal mucosal surface and therefore does not require penetration of intestinal epithelial cells. Intrauterine rubella requires entry of the virus, first into the mother’s circulation, and then into the fetal bloodstream. The other listed infec- tions all depend on penetration of an epithelial surface.
Short notes answers
- The main topic areas of bulk effect, altered function, toxin-mediated effects and host response should be covered, with examples.
- Could be tackled as a table. Follow the sequence of acquisition, colonisation, penetration, spread and damage. Give examples of bacteria and viruses.
- Follow principal routes of transmission and means of penetration; probably best done using a system-based approach.
Answers
Self-assessment: answers
Master Medicine
Answers
Viva answers
- Briefly define the two terms, then give specific examples and discuss how confusion of the two terms can cause problems in clinical practice.
- Some microbes have not yet been shown to cause human infection. Mention the spectrum of virulence from opportunist to those that can be highly lethal in the previously healthy
patient. Refer to the balance between patient and microbe and its modification by host defences, antibiotics and environmental factors. Give specific examples of how concepts of pathogenesis have changed recently through developments in molecular and cell biology and now challenge a simplistic pathogen–non-pathogen dichotomy.
