1. Chapter 4 Bacterial Infection and Pathogesis

2. 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.

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

4. 1. Normal Microbial Flora
the population of microorganisms that inhabit the skin and mucous membranes of healthy normal persons.

5. 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.

6. 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 stimulate 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.
__ To produce disease under certain circumstances : If forcefully removed from the restrictions of certain environment and introduced into foreign locations, they may become pathogenic.

7. Numbers of bacteria that colonize different parts of the body
Numbers of bacteria that colonize different parts of the body. Numbers represent the number of organisms per gram of homogenized tissue or fluid or per square centimeter of skin surface

8. Normal microbial Flora

9. The normal flora competes with invading pathogens.

10. Clinical conditions that may be caused by members of the normal flora

11. Infection No Infection Carrier Inapparent Infection Latent Infection
Acute infection/chronic infection）
Local infection/generalized infection or
systemic infection
Toxemia; Endotoxemia; Bacteremia;
Septicemia; Pyemia

14. 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.

15. 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”).

16. Pathogenicity: The ability of an infectious agent to cause disease.
Toxigenicity: The ability of a microorganism to produce a toxin that contributes to the development of disease.
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 )

17. Source of infection
Exogenous infection : patient, carrier, diseased animal or animal carrier.
Endogenous condition : most are normal flora, cause infection under abnormal condition.

18. TRANSMISSION OF INFECTION
Airborne droplets
Food
Water
Sexual contact

19. THE INFECTIOUS PROCESS
Mucous membranes
Respiratory tract
Gastorintestinal tract
Genitourinary tract
Skin
Parenteral route

21. THE CLONAL NATURE OF BACTERIAL PATHOGENS

22. 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:

23. BACTERIAL VIRULENCE FACTORS

25. Adherence Factors

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

28. 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)

30. Adhesion
BACTERIUM
adhesin
receptor
EPITHELIUM

31. S. pyogenes
lipoteichoic acid
F-protein
fibronectin

32. E. coli with fimbriae

33. E. coli fimbriae
Type 1
mannose P
galactose
glycolipids
glycoproteins

34. Invasion of host cells & tissues

36. Toxins Endotoxins Exotoxins 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.

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

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

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

40. Shiga toxin - shigellosis Shiga-like toxin - enterohemorraghic E. coli
Lyses rRNA in ribosome
Death of epithelial cells
Poor water absorption
Diarrhea

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

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

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

44. Membrane damaging toxins
Proteases
Phospholipases
Detergent-like action

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

46. Exotoxins
Antibodies (anti-toxins) neutralize
vaccination

47. 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

48. Endotoxins Endotoxin effects Lethal 1 milligram/ kg
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

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

50. Endotoxemia

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

53. 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

54. 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.

55. Antiphagocytic Substances
1. Polysaccharide capsules of S. pneumoniae, Haemophilus influenzae, Treponema pallidum ; B. anthracis and Klebsiella pneumoniae.
2. M protein and fimbriae of Group A streptococci
3. Surface slime (polysaccharide) produced as a biofilm by Pseudomonas aeruginosa
4. O polysaccharide associated with LPS of E. coli
5. K antigen (acidic polysaccharides) of E. coli or the analogous Vi antigen of Salmonella typhi
6. Cell-bound or soluble Protein 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.

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

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

58. Intracellular parasite
lysozome
phagosome
No fusion
Fusion
Enter cytoplasm

60. 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.

61. 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.

62. 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.

63. bacterial siderophores compete effectively for Fe3+ bound to lactoferrin and transferrin.