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Introduction to Microbial Pathogenesis

Introduction to Microbial Pathogenesis. Infectious Agent. (Proposed by Henle in 1840; demonstrated by Koch in 1876). “a single [type] of micro-organism could be isolated from all animals suffering from anthrax;

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Introduction to Microbial Pathogenesis

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  1. Introduction to Microbial Pathogenesis

  2. Infectious Agent (Proposed by Henle in 1840; demonstrated by Koch in 1876) • “a single [type] of micro-organism could be isolated from all animals suffering from anthrax; • the disease could be reproduced in an experimental host by infection with a pure culture of this bacterium; and • the same [type] of micro-organism could subsequently be reisolated from the experimental host.”

  3. Infectious Agents in Humans • Prion - scrapie • Viruses – HIV, influenza • Bacteria – Mycobacterium tuberculosis • Fungi – Candida albicans • Protozoa – Plasmodium falciparum • Helminths – Schistosoma mansoni

  4. Prion normal abnormal

  5. Virus

  6. Bacteria

  7. Fungi

  8. Protozoa

  9. Helminths Ascaris lumbricoides : human intestinal roundworm

  10. Barriers Physical barrier: Skin, Mucosal gel overlaying epithelium (respiratory, gastrointestinal, urogenitary) Microbiological barrier: Normal microbioflora

  11. Initiation of Disease

  12. Initiation of Disease • contact with pathogenic organism: • human to human, animal to human

  13. Transmission • Aerosols to respiratory mucosa • Fomite to nasopharyngial or conjungtive mucosa • Fecal – Oral Route • Mucosal surface to mucosal surface

  14. Infectious Disease Cycle Transmission Dissemination Breach of epithelium or Evasion of host defense Colonization of mucosa Multiplication Attachment to target cells Invasion to subepithelial or intracellular space

  15. Adherence/Attachment Specific Adherence Non-specific Adherence • Hydrophobic/lipophilic-mediated adhesion • Hydrophobic struture on microbial cell envelope • Lipophilic area on host cell membrane • Receptor-mediated adhesion

  16. Specific Adherence Microbial adhesin Host cell receptor Bacterial Epithelial cell Uropahogenic E coli Fimbrial P-pili glycolipid receptor globobiose Staphylococcus aureus Epithelial, endothelial, fibroblastic cells Afimbrial fibronectin receptor integrin fibronectin binding protein Herpes simplex 1 virus Epithelial cells of skin and mucosa glycoproteins B, C and D heparin sulfate Viral Epithelial, endothelial cells, mononcytes-macrophages (and others) Measles virus hemagglutinin (H) protein CD46

  17. Invasion bacterial viral • Transcytosis across superficial epithelium to subepithilial space • Induce engulfment by non-phagocytic host cells • Local reararrangement of host cell cytoskeleton • Phagocytosis • Utilization of membranous cell gateway • Pass through plasma membrane • Membrane invagination • Clathrin • Fusion with host cell plasma membrane • HIV gp120/41 • T lymphocyte CD4 • Macrophage CCR5

  18. Evasion/Manipulation of Host Defense • Modulation of innate/inflammatory response • Resistance to phagocytic killing in subepithelial space • Serum resistance • Antigenic variation

  19. histamine proteoglycans cytokines mast cell Modulation of Innate/Inflammatory Response Adhesin-directed degranulation of mast cells degranulation E. coli bound to mouse mast cell

  20. Inhibit phagocyte mobilization :(chemotaxis, complement activation) Inhibit chemoattractants: Streptococcus pyogenes degrades C5a Inhibit chemotaxis: Pertussis toxin causes intracellular rise in cAMP in neutrophils to impair chemotaxis • Avoid ingestion kill phagocytes: Streptolysin O lyses PMNs; Staphylococcus aureus alpha, beta and gamma toxins and leucocidin lyses PMNs capsular protection from opsonization: M proteins, Streptococcus pyogenes Bacterial capsules that resemble self: Neisseria meningitidis (sialic acid); Streptococcus pyogenes (hyaluronic acid) Resistance to phagocytic killing in subepithelial space • Survive within phagocyte

  21. Survival within phagocyte • Escape endosome or phagolysosome: • - Shigella, Listeria monocytogenes • Inhibit phagosome-lysosome fusion • Legionella pneumophila, Mycobacterium tuberculosis, Salmonella • Survive within phagolysosome(resist enzymatic degration or neutralize toxic products) • - Inactivate reactive oxygen species: Salmonella, via superoxide dismutase, catalase, recA • - Resist antimicrobial peptides: Host cationic peptides complexed with SapA peptide

  22. Antigenic variation Phase variation Genetic variation Transmission of genetic information via mobile genetic elements Gene recombination - Pili genes: Neisseria gonorrhoeae Gene reassortment - Influenza viruses A, B, C High mutation rate - RNA virus: Influenza viruses A, B, C Recombination of replication products - DNA virus: terminal redundancy in linear genome VSG in Trypanosoma brucei

  23. Cell and Tissue Damage • Induction of apoptosis and necrosis • Virus-induced cytopathic effect • Induction of damaging host immune response

  24. Induction of apoptosis Phase variation Genetic variation Transmission of genetic information via mobile genetic elements Gene recombination - Pili genes: Neisseria gonorrhoeae Gene reassortment - Influenza viruses A, B, C High mutation rate - RNA virus: Influenza viruses A, B, C Recombination of replication products - DNA virus: terminal redundancy in linear genome VSG in Trypanosoma brucei

  25. Induction of Cell Death Induction of apoptosis Induction of necrosis • Virus-induced apoptosis: • HIV (CD4+ T cell), EBV, adenoviris • Interfere with cellular regulation of cAMP • Bordetella pertussis (macrophage) • Activation of caspase-1 • Salmonella (macrophages, DC) • SipB binds and activates caspase-1 • Sigella flexneri (macrophages) Invasion Plasmid antigen B (IpaB) binds and activates host caspase-1 Bacterial toxins: Diptheria A-B toxin

  26. Virus-Induced Cytopathic Effect: Part 1

  27. Virus-Induced Cytopathic Effect: Part 2

  28. Induction of Damaging Host Immune Response

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