209 12-02-24

Pathogens

• Pathogens are microorganisms that cause disease
• Successful pathogens must accomplish entry, adherence, avoidance, growth, and exit.

Pathogenesis Overview

• Entry: Pathogens attach to the host using specific receptors, determining the initial infection site.
• Adherence: Pathogens must attach to their host. Special receptors determine the site of infection.
• Avoidance: Pathogens must avoid the host's defenses; rapid immune responses will eliminate them before they can replicate.
• Growth: Growth is linked to host damage.
• Exit: Transmission to a new host is the final stage.

Pathogen Virulence Factors

• Pathogens acquire virulence genes (e.g., for toxins and adhesins) through horizontal gene transfer.
• These genes are often clustered on 'pathogenicity islands', distinguishable by different G-C base-pair content from the surrounding genome.
• For example, E. coli O157/H7 acquired a Shiga toxin gene from Shigella, making it pathogenic.

Pathogen Attachment

• Bacterial structures: Pili (fimbriae) are surface proteins with attachment subunits (adhesins). Different species have different pili, binding to host cell carbohydrate structures.

  • Pili tip proteins determine binding specificity.
  • Type I pili, capped with FimH, bind mannose on intestinal epithelium.
  • Type I pili, capped with PapG, bind digalactose on urinary tract epithelium.
  • Type IV pili are dynamic, extending and retracting to pull bacteria close to host cell membranes.

• Non-pili adhesins: These are distinct bacterial surface proteins that bind to host cell proteins used for cell-to-cell contact.

  • Example: Bacterial Pertactin binds host cell integrins.
  • Streptococcal M protein also acts as an adhesin.

Biofilms

• Most organisms live in biofilms.
• Coordinate production of extracellular polysaccharide (EPS) forms a highly adhesive matrix.
• Biofilms create barriers that block immune mediators.
• Biofilms contribute to infections: oral, lung, bladder; and pose problems for in-dwelling medical devices.

Toxin Production

• Pathogen growth relies on toxins that disrupt host cell function or lead to cell death.

• Exotoxins: Secreted by pathogens.

• Endotoxins: Released from dead Gram-negative pathogens.

• Types of toxins:

  • Membrane disruption: Examples include alpha-toxin, a hemolysin.
  • Inhibiting protein synthesis: Example includes Shiga toxin.
  • Disrupting signal transduction: Example is Cholera toxin
  • Cell cycle disruption: Example is cytolethal distending toxins.

Type III and Type II Secretion Systems

• Bacteria employ secretion mechanisms to deliver virulence factors.
• Type III systems directly inject factors into host cells.
• Type II systems secrete factors into the extracellular environment.

A-B Toxin Structure

• Many toxins have an A-B structure:
  • B subunit binds host cell surface.
  • A subunit exerts toxic effect inside the cell after transport

Cholera Toxin

• Vibrio cholerae secretes cholera toxin (a very similar toxin is also made by Entertoxigenic E. coli).
• This toxin causes diarrhea.
• It induces chloride secretion by activating a chloride channel and disrupting nutrient uptake.
• It binds to GM1 ganglioside of intestinal cells. The released A subunit triggers a CAMP increase, activating a chloride channel, which increases ion secretion and diarrhea.

Sepsis

• Sepsis is a serious, blood-borne bacterial infection.
• Mortality from sepsis is high (17%) compared to other conditions (2%).
• Rapid diagnosis is critical for survival.
• Incidence of sepsis is increasing with population aging.

Microbial Pathogen Life Styles and Immune Responses

• Microbial pathogens have diverse life styles (extracellular, intracellular).
• Whatever the lifestyle, pathogens avoid or block the host immune response to be successful.