Pathogen Structures & Mechanisms PDF

What’s a pathogen? What traits does a pathogen need? Where do pathogens come from?  Overview of pathogenesis All pathogens must accomplish the following in order to be successful: -Entry -Adherence: they must attach to their host, usually using specific receptors that determine...

What’s a pathogen? What traits does a pathogen need? Where do pathogens come from?  Overview of pathogenesis All pathogens must accomplish the following in order to be successful: -Entry -Adherence: they must attach to their host, usually using specific receptors that determine the initial site of infection. -Avoidance: they must avoid host defenses or rapid immune responses will eliminate them before they can replicate. -Growth: associated with host damage. -Exit: transmission to a new host. Tricia at the fair….. She is infected by E. coli O157/H7 which causes hemolytic uremic syndrome. This pathogenic strain of E. coli is very similar to non-pathogenic E. coli but has acquired the gene for Shiga toxin which originated in Shigella. In general terms what describes the role of this toxin in E. coli O157/H7 pathogenesis? How did E. coli get this gene from Shigella? Pathogens can acquire genes for virulence factors as a result of horizontal gene transfer. Often these genes are found clustered together in ‘pathogenicity islands’. Pathogenicity islands contain clusters of genes that specify virulence factors such as adhesins, toxins, and export proteins. Evidence that they originated in other organisms comes from the observation that often their overall G-C base-pair content is different from the surrounding genome. What pathogen structures mediate attachment? What do viruses use for attachment? Virus infection is very specific. Viruses bind and infect particular cell types (tissue tropism), in particular species (host range), by binding to specific cell surface receptors. Enveloped viruses bind cell receptors using glycoproteins in the envelope, while non-enveloped viruses use capsid proteins.  Bacterial Adhesins: Pili (also called fimbriae) are bacterial surface proteins capped with a unique attachment subunit (adhesin). Different species have different pili that bind to unique carbohydrate structures on host cells. E. coli cells The protein at the tip of the pili microvilli determines (not pili) binding specificity Intestinal Cell Type I pili are fixed on the bacterial surface. Type I pili capped with FimH bind mannose on intestinal epithelium. PapG capped pili bind digalactose residues on urinary tract epithelium. Type IV pili are dynamic -they extend and retract as pili assemble and disassemble. The end of the pili mediate adherence. Retraction pulls the bacteria close to the host cell membrane.  Non-pili adhesins are a distinct class of bacterial cell-surface protein fibers that mediate attachment to host cells. These adhesins typically bind to proteins that host cells use for cell- cell contact, e.g. bacterial Pertactin binds host cell integrins. Streptococcal M protein adhesin. Pertactin is a Bordetella pertussis adhesin that mediates binding to respiratory epithelium. Most organisms exist in biofilms which provide non-specific adherence. Coordinate production of extracellular polysaccharride forms a highly adhesive matrix. Biofilms also create a barrier blocking the action of immune mediators. Biofilm formation plays an important role in oral, lung and bladder infection, as well as posing a serious problem for in-dwelling medical devices. Pathogen growth is reliant on the production of toxins that disrupt host cell function or lead to cell death. Exotoxins are secreted by pathogens, while Endotoxin is released during the breakdown of dead Gram(-) pathogens.  Bacteria use a variety of secretion mechanisms to deliver virulence factors. The Type III system can inject factors directly into host cells, while the Type II system secretes them into the extracellular environment. Type III system directly attaches to the host cell Type II system uses a piston to membrane to deliver factors. deliver factors to the extracellular environment Many toxins have an “A-B” type structure: they are composed of A and B subunits where the B subunit binds the host cell surface and helps transport the A subunit which acts on specific intracellular targets.  Vibrio cholerae is a primary pathogen that adheres to the surface of intestinal cells and secretes cholera toxin, an enterotoxin that causes diarrheal disease. Entertoxigenic E. coli produces a very similar toxin, Labile toxin (LT). Vibrio cholerae Many enterotoxins activate export of chloride from enterocytes into the lumen of the intestine which blocks uptake of nutrients and leads to secretion of water producing diarrhea. Cholera toxin binds to the GM1 ganglioside present on the surface of intestinal cells via its B subunit and is endocytosed. The released A subunit induces an increase in cAMP levels that activate a Chloride channel, inducing ion secretion and diarrhea.  Alpha toxin is an example of a hemolysin that can kill host cells by disrupting membranes. The toxin forms pores in host cell and vesicle membranes. Efflux of Cytplasmic cytoplasmic components membrane Out a-toxin pore In Influx of extracellular components Hemolysins are named for their ability to lyse erythrocytes in blood agar plates. Production of the toxin is detected by clearing around colonies. Shiga toxin: an A-B type toxin that can kill cells by inhibiting protein synthesis Super antigens secreted by pathogens stimulate a large proportion of helper T cells. The activated T cells produce massive amounts of cytokines and a systemic inflammatory response. Toxic shock syndrome is caused by these toxins. Chapter 16.7 Super antigens stimulate T cells independent of the specificity of the T cell antigen receptor.  Endotoxins Endotoxins are LPS related products released from Gram negative pathogens as they are broken down. The endotoxin acts on immune cells inducing secretion of inflammatory cytokines and causing fever.  Hospitalization with sepsis is increasing Sepsis-blood-borne bacterial infection, is a very dangerous condition. Sepsis rate increases with age Mortality associated with hospitalization for sepsis is 17%, compared to 2% for other diagnoses. Key to survival is rapid diagnosis. Incidence of sepsis has increased, and is likely to continue as the population ages. Microbial pathogens have a variety of life styles which elicit a variety of immune responses. Whatever their lifestyle, in order to be successful pathogens need to avoid, or block, the host immune response.