What is pathogenesis Describe the stages through which pathogenesis typically proceeds PDF

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What is “pathogenesis”? Describe the stages through which pathogenesis typically proceeds Pathogenesis is the steps in which a pathogen such as bacteria (shigella, salmonella, cholera, EPEC) take in order to bring about a onset of infection and disease, i.e. entry/transmission, colonization/survival/spread, evasion of host defence mechanisms, tissue injury and eventual exit. Therefore, it is the way or manner in which a pathogen causes disease. Several barriers of the body exist which mediate the entry of pathogens from entering the body for example the skin. Microorganisms are able to enter through the mouth (alimentary canal/GI/respiratory tract), anus/genital openings (urogenital tract). The eyes are not covered by skin so living cells (conjunctiva) perform same function as skin in eyes. Both the conjunctiva and urogenital tract are the easiest to penetrate, so have antimicrobial systems to prevent penetration i.e. cleansing systems. Different organisms have differing methods of entry, either ingression or penetration (into deeper tissue after crossing the epithelial barrier), for example the use of adhesins which determine where the pathogen binds and enters the host (depends on corresponding receptor), with bacteria adhesins being Pili, slime, capsule, lipotechoic acid (corresponding host cell receptors are fibronectin, mannose receptors, sialic acid receptors and also glycoproteins). An example is B.pertussis toxin B which has S2 and S3 subunits, these bind to surfaces on macrophages and result in upregulation of CR3, CR3 binds to another adhesin on B pertussis (FHA) and causes intake of bacterium. The skin can be a route of entry but is a less accessible than others, typically commensal micororganisms are neutralised to prevent pathogenesis by fatty acids and skin pH of around 5.5 in addition to sebum and other commensal i.e. perianal region, billions of faecal bacteria inactivated. Shaving (also surgery and pre-operatives) can lead to disruption in antimicrobial defences, leading to S.aureus infection. Also, animal and insect vectors can penetrate the skin through bites such as antropods and transmission of malaria (passed through saliva), or the classic example of rabies virus being shed in the saliva of infected dogs, foxes, wolves, vampire bats. The respiratory tract is also a key entry point in pathogenesis, which provides several tests which microorganisms need to pass to survive. These are, avoid being caught in the mucus, which can be done through a defective mucolillary action/escalator, or a special attachement protein i.e. influenza has haemagluttin which attaches to neuraminic acid on epithelial cells, rhinovirus has an adhesion molecule ICAM-1 or LDLR, S.aureus binds to TNFR1 on epithelial cells. The second is if deposited in alveoli, to avoid phagocytosis by alveolar macrophages and lastly if phagocytosed, must survive and multiply. Therefore, bacteria lacking in these mechanisms can only cause damage in the absence or a defective mucociliary cleansing mechanism becomes prevalent (possible by viral intervention). For instance, parainfluenza induces destructive lesions, which then bacteria such as streptococci can colonize in the lung and produce a secondary pneumonia. Examples of microorganisms causing mucociliary defects are; M.pneumoniae which multiplies while attached to the surface of epithelial cells and produces H202 to cause a cilliostatic effect (stop cilia beating), haemophilus influenza produces a factor which slows

the ciliary beating and interferes with ciliary coordination, causing a loss in cilia. The gastrointestinal tract, is always in motion unlike the RT, viruses such as poliocoxsackie and echoviruses multiply in the GI tract epithelial cells by forming firm unions with receptors in epithelial cell surface, allowing penetration of cells by membrane fusion or endocytosis. In addition, enteric bacteria can increase their numbers in the lumen before entry into the epithelial cells. Patients who are taking broad-spectrum antibiotics, show changes in their normal intestinal flora allowing growth of certain microorganisms leading to disease such as in the case of candida albicans and clostridium dificile. Pathogenicity islands are integral parts of pathogenic genomes which code for virulence factors e.g. toxins, adhesins, invasins, iron uptake systems and secretion systems. Four notable secretory systems found in gram negative bacteria are; Type 1 which are sec-independent (secretory pathway) uses proteins to export proteins outside of the cell from the inner/outer membrane i.e. ABC, MFP and outer membrane pore forming protein (OMP). Type II sec dependent – secretes from intermembrane space across the outer membrane only, type III sec independent – related to flagella assembly system, Type IV – secretes proteins in which proteins contain all information for transmembrane negotiation. Some notable pathogens which have distinct pathogenesis are Enteropathogenic E.coli (EPEC), shigella virus, salmonella and vibrio cholera. EPEC can cause severe diarrhoea but is not invasive and rarely found in gut epithelial cells. Virulence is controlled by 2 genetic factors, the BFP genes (bundle forming pili) which is encoded in the adherence factor plasmid (EAF) and the LEE PI (locus of enterocyte effacement) in the EPEC chromosome (LEE is more important for EPEC colonization). Plasmid encoded regulator (PER) regulates expression of these genes in the EAF plasmin. When EPEC comes into contact with epithelial cells, expression of LEE is triggered and translocon formation occurs. This translocon consists of a pore being created in the host membrane in which the EPEC injects a protein called Tir through a tube. Tir is phosphorylated in the host cell and displayed on the host cell surface. This tube then retracts bringing EPEC and the host cell together, the Tir then binds to intamin (EPEC surface), resulting in microvilli effacement (removal) and actin formation in the host cell cytoplasm. Actin formation causes elevation of the EPEC causing diarrhoea.

The second stage in pathogenesis is colonisation, survival and spread or in other words attain a niche, in which the pathogen can grow on a particular tissue, cell or locality. Many microorganisms multiply on the epithelial surface due to the liquid medium coverage (such as in respiratory and intestinal infections), this is due to the ease of dissemination over the surface and spread (skin is less applicable and takes a longer time). Most bacteria unable to overcome host defences and invade further into tissues to host antimicrobial defences, however gono/streptococci infections spread locally through tissue (occasionally systemically). An example of epithelial-surface restricted systemic bacterial infection is Group A streptococcus which causes necrotizing fasciitis. Most Gram –ve bacteria have a limited capacity to invade a host; E.coli or pseumdomonas aeruginosa only able to invade once immune defences are impaired or enter a specific site, causing sepsis in uterus after abortion. Shigella for example can penetrate intestinal epithelium, but get no further,

whereas salmonella typhi is able to go further, entering the lymphatics and spread systematically (causing enteric or typhoid fever). One factor which may restrict spread is temperature, with some mycobacterium optimum growth of 30-33C is needed, thus remain on skin only (chronic skin ulcers). For pathogens to spread, entering of the blood or lymphatics is integral, thus gaining access to sub-epithelial lymphatic/blood vessel or infect mobile cell (leucocyte). Measles virus and tubercle bacilli infect leucocytes, so they can travel to liver, spleen, skin and lung. Some pathogens can multiply outside host cells and thus in the blood or lymph, however this then exposes the pathogen to all antimicrobial defences of host, especially considering bacterium have antigens which can be detected and produce bacterial proteins thus leading to inflammation of Ig antibodies, complement activation and WBCs. Three host defence mechanisms are tissue fluid, lymphatic system, and phagocytic cells. Tissue fluid can be apparatus in which antibodies (IgG) and complement can pass through in response to inflammation from endotoxins activating the alternative complement pathway. Later, lysozymes and oxygen radicals from phagocytes can also be secreted from platelets, neutrophils and macrophages. The lymphatic system becomes activated as host mechanism, increasing lymph flow in response to inflammation (dilation), this allows for increase circulation of macrophages lining marginal sinus to phagocytose pathogens, if microorganisms evade this they then face intermediate sinus macrophages. Neutrophils can also join in on the attack. The last host defence mechanism is phagocytic cells; macrophages and neutrophils, upon inflammatory response, they bring phagocytes and serum factors to site of infection and promotes lymphatic drainage. However, if pathogens survive in macrophage they can grow in them as a site of nourishment. The third stage in pathogenesis is evasion of host defence mechanisms, microorganisms have several strategies for which they do so. Several mechanisms are, inhibiting absorption, inhibiting phagocytosis and opsonisation, inhibiting fusion of lysosome with phagocytic vacuole, and escaping the phagosome. The inhibition of phagocytosis and opsonisation occurs in pneumococci which has M-like proteins (anti-phagocytic) in its polysaccharide capsules, which interfere with binding of factor H, disruption complement pathway and the incorrect biding of IgG to Fc receptors on circulating phagocytes, which are unable to recognise and bind to them (no opsonisation). In addition, neuraminic acid in its capsules prevents c3b binding without antibodies, thus preventing phagocytosis mechanically. Inhibiting fusion of lysosome with phagocytic vacuole occurs in salmonella typhimirium which inhibits this fusion and divides within unfused vacuoles. Escaping the phagosome occurs in shigella which can escape the phagosome and spread into adjacent enterocytes.

Specific microbial strategies have been developed against the immune system to cause damage, such as molecular mimicry, tolerance. Superantigens produced by some bacteria (strep and staph) and some viruses (retroviruses) bind to MHC II, which interact with T-cell receptors via the V-Beta chain. This binding of superantigen to TCRs induces T-cell proliferation and cytokine release. However if T-cells encounter these antigen early in development the T-cell will be deleted (lack of co-receptor presence and other proliferation mediators such as cytokines), so no T-cell with that V-beta chain is detected in the spleen or

lymph node. T-cells can also undergo anergy in the situation where a lack of dendritic and Bcell interaction. In chronic infection, viruses such as HIV and HepC, T-cells can suffer from exhaustion due to continuous stimulation (over months). Molecular mimicry can occur in the situation where host and pathogen antigens are similar in structure leading to a small or absent immune response. This is prevalent in streptococci strains which have a hyaluronic acid capsule, which is identical to a major component of mammalian connective tissue. Toxins can also be utilized by microorganisms which work at different points or areas of cells, for example extracellular, damage membranes, intracellular targets. The staphyloccal exfoliative toxins can lead to bullous impetigo and scalded skin syndrome (SSS). In SSS exfoliative toxins A and B cause cleavage of desmoglein-1 (adhesion molecule), which leads to skin becoming easily displaced upon minimum force applied, thus scalding. The pneumolysin (PLY) toxin (neurotoxin) is a cholesterol-binding cytolysin produced by s.pneumoniae which causes bacteraemia, pneumonia, meningitis and otitis media. PLY remains in the cytoplasm, until it is lysed open, the toxin itself has four domains which oligermise and form a pore post-cholesterol binding. The pathogenic properties of PLY are haemolytic activity, inflammation of lung and bloodstream invasion, alveolar permeability modulation, cilial inhibition of respiratory mucosa, and activation of complement classical pathway. Toxins with intracellular targets, cross the cytoplasmic membrane and have an effect on intracellular targets by one of three ways; self-translocation, direct injection and receptor-mediated endocytosis. Cholrea toxin (CT), shiga toxin (ShT) and shiga-like toxin (ShLT) are known as group two toxins as they have different genes which produce A and B fragments which can form stable complexes. Exit from the body can occur through several ways such as the respiratory tract, saliva, intentestinal tract/diarrhoea, urogenital tract, blood. The respiratory tract is one way in which pathogens can be expelled from the body i.e. shedding from coughing and sneezing so forcibly releasing the microorganism from the body (single sneeze expelling 20000 particles in the air, with majority being viral particles). Intestinal tract can expel microorganisms through normal faecal matter or diaarhoea in the case of infection....