Introduction to microbes and infectious disease Most microbes do NOT cause disease (what’s the difference, i.e., what

1. Introduction to microbes and infectious disease Most microbes do NOT cause disease (what’s the difference, i.e., what is a virulence factor?) Microbes cause different diseases (why?) How do microbes get into the body (portals of entry) and spread (portals of exit)?

2. Why do some organisms cause disease while others do not? Pathogens cause disease evade immune system cause tissue damage Other organisms harmlessly colonize the body (Ch. 22-28; why do organisms cause disease in a particular part of the body?)

3. p. 460

4. Resident? Transient? p. 461; locations for normal flora

5. Pathogenesis of infectious disease How does an organism cause disease? (impairment of function) What is the course of disease? How is disease spread? How is the organism shown to be pathogenic? Is it always pathogenic (primary pathogen) or only is susceptible people (opportunistic) How virulent is the infectious organism?

6. Contagious (communicable) diseases are easily spread Sometimes the infectious dose is very low (therefore easier to spread) Example: dose is high for Salmonella low for Shigella (both cause diarrhea) Infectious dose can be calculated

7. General sequence of events in infectious disease p. 463 Infection may be localized or systemic Time course can be short or long

8. Koch’s postulates- classical way to determine • if a particular organism causes disease • Microbe is present in all affected individuals • Organism is isolated from a sick individual • When organism is introduced into new hosts, • they get sick, too- and same organism is • isolated from them. • Not all organism can be grown in pure culture • or tested • Postulates are applied on molecular level • (what microbial product causes disease)

9. Mechanisms of pathogenicity Toxin production (endotoxin or exotoxin) toxins can be produced in body or ingested Colonization (usually GI or respiratory tract) acquire food, overcome normal flora Invasion of tissues (avoid immune system) Or some combination!

10. How do bacteria establish infections? Adhesion (adherence) is often a necessary first step Adhesins bind to specific molecules on cell surface- contributes to tissue specificity i.e., E.coli in urinary tract; Neisseria in repro- ductive tract

11. How do microbes invade body Skin- through lesions or vectors (bites) Many bacteria have developed ways to get through innate immune barriers or by crossing epithelia (cells specialized for engulfment and/or transport) Some bacteria hide inside host cells (e.g., Listeria)

12. Avoiding immune mechanisms Gram-positive organisms are not sensitive to complement-mediated lysis Some Gram-negatives use complement receptors or special glycosylation Avoiding phagocytosis capsules; complement inactivation streptococci, staphylococci

13. Surviving phagocytosis Listeria, Shigella get out of phagosome Salmonella- prevent fusion with lysosome IgA proteases Antigenic variation; mimicking host molecules (streptococci good at this)

14. Pathogenic mechanisms • Toxins • “A-B” (“B” attaches to cell (specificity); “A” part is the toxin • Cytotoxins damage cells membranes • Superantigens aggravate immune response • Other damage specific tissues

15. How do toxins damage host? (see p. 473) A-B toxins: examples I. Neurotoxins- interfere with transmission of nervous signal C. botulinum- prevents release of acetylcholine (flaccid) C. tetani- blocks inhibitory neurons spastic

16. II. Enterotoxins- oversecretion of fluids into intestine- E. coli; V. cholerae III. Cytotoxins B. anthracis, B. pertussis- oversecretion C. diphtheriae, E. coli O157:H7, S. dysenteriae inhibit protein synthesis

17. Membrane-damaging toxins have different structure, directly attacking cell membranes (Have different structure than A-B toxins) Example: hemolytic bacteria (can lyse other membranes beside RBC membranes)

18. Superantigens break the rules of antigen specificity (also act differently than other exotoxins) Recall that T cells recognize antigen “presented” to them by MHC Class II on APCs (see p. 475) Superantigens bind differently; can activate may different T cells simultaneously Excess stimulation can cause nausea, vomiting and sometimes shock S. aureus toxin is well characterized (TSS)

19. Most exotoxins are not heat-stable (except S. aureus superantigen) Many exotoxins have been isolated and are used (as toxoids) for vaccines See p. 477 for comparison with endotoxin

20. Endotoxin is actually component of Gram- negatives (LPS), so cannot be isolated like an exotoxin can Damage is due to inflammatory response to it can be fatal (septic shock) Heat-stable; not autoclavable Limulus amoebocyte assay is used to test for endotoxins

21. Thus immune response itself can contribute to disease Inflammation Hypersensitivity Autoimmune disease (cross-reactive antibodies) “Immune complex disease” can lead to kidney damage

22. Viral pathogenesis All viruses must live within cell; some can cause chronic or latent infections Viruses bind to specific receptors on cells and (in animals) are endocytosed May stick to one type of tissue or spread

23. Many viruses have evolved mechanisms that neutralize specific immune functions Influenza, HIV- avoid interferons (HIV-infects regulatory T cells!) Block MHC Class I expression Form syncytia (cells fuse together) Antigenic variation

24. How do viruses damage cells? Burst cells Apoptosis (avoids inflammatory response, too) Inflammatory response (Most, but not, rashes associated with infectious disease are caused by viruses)

25. Fungal infections Remember how fungi eat! Fungi can damage living tissue, too Effect is strong in immunocompromised patients Toxins Hypersensitivities

26. Helminths and protozoa Depends on organism and host tissue Malnutrition Damage to colonized tissue; dysfunction associated with that Can suppress immune response

27. Study of pathogenesis involves: Identification of virulence factors Understanding host range of organisms Normal host response to organism and how pathogen deals with it Strategies for prevention and treatment