Bacterial Infection and Immunity

1. Bacterial Infection and Immunity

2. Symbioses • Commensalism: one partner benefits and the other is neither harmed nor benefited. • Mutualism: both partners benefit. • Parasitism: one partner benefits at the expense of the other.

3. Role of the resident flora • Members of the resident flora in the intestinal tract synthesize vitamin K and aid in the absorption of nutrients. • Members of the resident flora on mucous membranes and skin may prevent colonization by pathogens and possible disease through “bacterial interference”. • The normal flora may antagonize other bacteria through the production of substances which inhibit or kill nonindigenous species. • The normal flora stimulates the development of certain tissues, i.e., the caecum and certain lymphatic tissues (Peyer's patches) in the GI tract • The normal flora stimulate the production of cross-reactive antibodies.

4. Hospital acquired infection • Infections acquired during hospital stays.

5. Pathgen: A microorganism capable of causing sisease. • Nonpathogen: A microorganism that does not cause disease; may be part of the normal flora. • Opportunistic pathogen: An agent capable of causing disease only when the host’s resistance is impaired (ie, when the patient is “immunocompromised”). • Pathogenicity: The ability of an infectious agent to cause disease

6. Virulence: The quantitative ability of an agent to cause disease. Virulent agents cause disease when introduced into the host in small numbers. Virulence involves invasion and toxigenicity. LD 50 (age /sex /health /route of entry, etc ) • LD50:The number of pathogens required to cause lethal disease in half of the exposed hosts is called an LD50. • ID50:The number of pathogens required to cause disease (or, at least, infection) in half of the exposed hosts is called the ID50

7. Adherence(adhesion, attachment): the process by which bacteria stick to the surfaces of host cells. Once bacteria have entered the body, adherence is a major initial step in the infection process. The terms adherence, adhesion, and attachment are often used interchangeably. • Invasion: The process whereby bacteria, animal parasites, fungi, and viruses enter host cells or tissues and spread in the body. • Toxigenicity: The ability of a microorganism to produce a toxin that contributes to the development of disease.

8. IDENTIFYING BACTERIA THAT CAUSE DISEASE • Koch’s Postulates • Molecular Koch’s Postulates • Molecular Guidelines for Establishing Microbial Disease Causation

9. Koch's postulates • Isolated • diseased not healthy people • Growth • pure culture • Induce disease • susceptible animals • Re-isolated • susceptible animals

10. Pathogenesis • Pathogenesis is a multi-factorial process which depends on the immune status of the host, the nature of the species or strain (virulence factors) and the number of organisms in the initial exposure.

11. BACTERIAL VIRULENCE FACTORS

12. REGULATION OF BACTERIAL VIRULENCE FACTORS Environmental signals often control the expression of the virulence genes. Common signals include: • Temperrature • Iron availability : C diphtheriae /low ion • Osmolality : • Growth phase: • pH: • Specific ions:

14. 1. Adherence Factors

16. Specific Adherence of Bacteria to Cell and Tissue Surfaces 1. Tissue tropism: 2. Species specificity: 3. Genetic specificity within a species:

17. Nonspecific adherence • Hydrophobic interactions • Electrostatic attractions • Atomic and molecular vibrations resulting from fluctuating dipoles of similar frequencies • Brownian movement • Recruitment and trapping by biofilm polymers interacting with the bacterial glycocalyx (capsule)

19. Adhesion BACTERIUM adhesin receptor EPITHELIUM

20. S. pyogenes lipoteichoic acid F-protein fibronectin

21. E. coli fimbriae Type 1 mannose P • galactose • glycolipids • glycoproteins

22. E. coli with fimbriae

23. 2. Invasion of host cells & tissues

25. 3. Toxins   • Exotoxins • Endotoxins Endotoxins • Produce in vitro cause food poisoning: botulin, staphylococcal enterotoxin, etc. • Produce in vivo: Systematic toxic effects : e.g. diphtheria, tetanus, and streptococcal erythrogenic toxins. Local toxic effects: e.g. cholera, and toxigenic E. coli enterotoxins.

26. A-B toxins Cell surface Active Binding A B

27. Diphtheria toxin and Pseudomonas exotoxin A • ADP-ribosylate elongation factor (EF2) • inhibit protein synthesis

28. Cholera toxin and E. coli labile toxin • ADP-ribosylate adenylate cyclase • cyclic AMP • active ion and water secretion • diarrhea

29. Shiga toxin - shigellosis Shiga-like toxin - enterohemorraghic E. coli • LysesrRNA in ribosome • Deathof epithelial cells • Poorwater absorption • Diarrhea

30. Tetanus toxin • inhibits glycine release • inactivates inhibitory neurons • muscles over-active • rigid paralysis

31. Botulinum toxin • inhibits acetylcholine release • inhibits nerve impulses • muscles inactive • flacid paralysis

32. Exotoxins - extracellular matrix of connective tissue • Clostridium perfringens - collagenase • Streptococcus - hyaluronidase

33. Membrane damaging toxins • Proteases • Phospholipases • Detergent-like action

34. C. perfringens phospholipase • Destroys blood vessels • Stops influx inflammatory cells • Creates anaerobic environment • Allows growth of this strict anaerobe.

35. Exotoxins • Antibodies (anti-toxins) neutralize • vaccination

36. Endotoxins • LPS Lipopolysaccharide: core or backbone of CHO side chains of CHO: "O" antigen Lipid A • Cell wall lysis required • formaldehyde and heat resistant • poor antigen as free molecule

37. Endotoxins • Endotoxin effects Fever-pyrogen 1 microgram/ kg Leukopenia and leukocytosis necrosis Shwartzman phenomenon and disseminated intravascular coagulation (DIC). Endotoxemia and shock • Lethal 1 milligram/ kg • Identification :Limulcyte assay

38. Endotoxins • Non-specific inflammation. • Cytokine release • Complement activation • B cell mitogens • Polyclonal B cell activators • Adjuvants

39. Endotoxemia

41. Peptidoglycan of Gram-positive bacteria • May yield many of the same biologic activities as LPS.

42.   4. Enzymes • Tissue-degrading enzymes • IgA1 proteases: split IgA1, an important secretory antibody on mucosal surfaces, and inactivate its antibody activity. • H. influenzae • S. pneumoniae • N. gonorrhoeae • N. meningitidis

43. 5. Antiphagocytic factors • Some pathogens evade phagocytosis or leukocyte microbicidal mechanisms by adsorbing normal host components to their surfaces. A few bacteria produce soluble factors or toxins that inhibit chemotaxis by leukocytes and thus evade phagocytosis.

44. Antiphagocytic Substances • 1. Polysaccharide capsulesof S. pneumoniae, Haemophilus influenzae, Treponema pallidum; B. anthracisand Klebsiella pneumoniae. • 2. M protein and fimbriaeof Group A streptococci • 3. Surface slime (polysaccharide) produced as a biofilm by Pseudomonas aeruginosa • 4. O polysaccharideassociated with LPS of E. coli • 5. K antigen(acidic polysaccharides) of E. coli or the analogousVi antigenof Salmonella typhi • 6. Cell-bound or solubleProtein A produced by Staphylococcus aureus. Protein A attaches to the Fc region of IgG and blocks the cytophilic (cell-binding) domain of the Ab. Thus, the ability of IgG to act as an opsonic factor is inhibited, and opsonin-mediated ingestion of the bacteria is blocked.

45. Protein A inhibits phagocytosis PHAGOCYTE Fc receptor Protein A immunoglobulin BACTERIUM

46. r r r M protein inhibits phagocytosis Complement fibrinogen M protein peptidoglycan

47. 6. Intracellular pathogenicity • Some bacteria live and grow within polymorphonuclear cells, macrophages, or monocytes by avoiding entry into phagolysosomes and living within the cytosol of the phagocyte, preventing phagosome-lysosome fusion and living within the phagosome, or being resistant to lysosomal enzymes and surviving within the phagolysosome.

49. 7. Antigenic heterogeneity • Antigenic type of bacteria may be a marker for virulence, related to the clonal nature of pathogens, though it may not actually be the virulence factor. • Some bacteria may make frequent shifts in the antigenic form of their surface structures in vitro and presumably in vivo, allowing the bacteria to evade the host’s immune system.

50. 8. The requirement for iron • For the host, the iron metabolism denies pathogenic bacteria an adequate source of iron for growth. • For the bacteria, they have developed several methods to obtain sufficient iron for essential metabolism, e.g., the low-affinity iron assimilation system or the high-affinity iron assimilation systems.