Mechanisms of Pathogenesis

A. When does a potential pathogen cause disease?

1. Virulence of the pathogen
   1. Virulence factors
      1. Quorum sensing
      2. temperature
   • Temperate bacteriophages (C. diphtheriae)
   • Pathogenicity islands (E. coli, Salmonella, Pseudomonas)
   • Plasmids (B. anthracis, C. tetani)
2. Number of pathogens present: ID50
   • Salmonella: ~ 1,000,000
   • Shigella: ~ 200
   • Vibrio: ~ 100,000,000
3. Location/entry point of the pathogen
   • Blood stream infections (BSI)
   • CNS infections
   • Intestinal perforation
4. Host defenses / immune system status
   • Immune suppression
   • Gastric pH imbalance
   • Cystic fibrosis
5. Duration of the infection
   • Acute vs chronic

B. Pathogenesis - why do we get sick?

1. Mere presence/growth of a microorganism
   • Elephantiasis (Filariasis) - obstruction of lymphatics
2. Immune system response (Immunopathogenesis)
   • Acute-phase response to LPS: sepsis
   • Inflammation: Lyme disease
   • Antibody cross-reaction: rheumatic fever
   • Granuloma formation: tuberculosis
   • Viral infection: cytokine release
3. Invasiveness / Tissue destruction
   • Fermentation products
     • Acid & Gas: Gas gangrene (C. perfringens)
   • Enzymes
     • Phospholipase C (alpha toxin)
     • collagenase
     • hyaluronidase
     • fibrinolysin
     • lipase
     • streptolysin
     • DNAse
     • protease
4. Endotoxins
   1. LPS of Gram-negative bacteria
   2. Lysis releases LPS - activates cytokines
      • IL-1, IL-6, TNF, prostaglandin
      • fever, septic shock, capillary leakage, inflammation
      • intravascular coagulation (DIC) & complement activation
5. Exotoxins
   1. Heat sensitive proteins
   2. Highly toxic by themselves
   3. Secreted by bacteria; may enter circulation
      • Cholera toxin: activates G-protein + adenylate cyclase
      • Pertussis toxin: inactivates G-protein, activates adenylate cyclase
      • Diphtheria toxin: inactivates EF-2, blocks protein synthesis
      • Botulinum toxin: blocks exocytosis of acetylcholine
      • Tetanus toxin: blocks release of inhibitory neurotransmitters
      • Cytolysins (e.g. lecithinase) - gas gangrene
      • Hemolysins: lyse red blood cells
      • Anthrax toxins (EF, LF, PA) - cause edema, cell death
      • Shiga toxin (Shigella dysenteriae) - inhibits protein synthesis
      • Enterotoxins: LT, ST
6. Superantigens
   • Activate T-cells without need for a specific antigen
   • Release of IL-1 (fever) & IL-2, TNF (hypotension/shock), death of T-cell
   • Example: 
     • Staphylococcus TSS toxin & enterotoxin; 
     • S. pyogenes erythrogenic toxins
7. Viral infection
   1. Cell  lysis
      • Inhibit cellular DNA synthesis & degrade host cell DNA (HSV)
      • Inhibit host cell protein synthesis (polio, HSV, poxviridae)
      • Cell membrane alterations (enveloped viruses)
   2. Cell fusion - syncytia formation (HSV, HIV, Paramyxoviridae)
   3. Inclusion bodies
      • Negri bodies (Rabies)
      • Owl's eye (CMV)
      • Cowdry intranuclear inclusions (HSV)
   4. Immunopathogenesis
      • Cytokines & interferon: flu-like symptoms
      • Type III hypersensitivity & inflammation: mumps, measles, hemorrhagic fevers
      • Immune complex formation: rubella, HBV
   5. Latency: HSV
   6. Persistent infection: Many enveloped viruses
   7. Transformation - cancer (oncogenic viruses)
      • activation of cellular genes (EBV)
      • deactivation of cellular control signals s.a. p53 (HPV)
      • inhibition of apoptosis (EBV)
      • viral genes which activate growth (non-human retroviruses)
      • insertion of viral DNA near growth-promoting human genes (HTLV)
      • tissue damage that necessitates frequent cell division (HBV)

   * Why do children exhibit less severe symptoms to mumps, measles and chickenpox than adults?

8. Fungal infection 
   1. Colonization of the host
      • Immune system evasion or deficit
      • Growth and/or dissemination
   2. Obstruction: blood vessels, lungs (Aspergillosis)
   3. Hydrolytic enzymes: proteinase, elastase, phospholipase
   4. Immunopathogenesis: inflammation (Ringworm), granuloma formation (mycetoma), immune complexes (Coccidiodomycosis), abscess (Candidiasis)
   5. Tissue damage: lesions, fibrosis, edema
9. Parasitic infection
   1. Hydrolytic enzymes: proteinase, elastase, collagenase
   2. Ionophores (Entamoeba)
   3. Endotoxins (Trypanosoma)
   4. Obstruction (Ascaris)
   5. Migration of larvae (flukes)
   6. Immunopathogenesis: inflammatory (Trypanosoma), immune complexes (Malaria)

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