molecular mechanism of pathogenesis

Molecular mechanism of pathogenesis

1. Pathogenesis & Microbial Mechanisms of Pathogenesis

2. Pathogenesis The word comes from the Greek pathos , "disease", and genesis , creation. The term pathogenesis means step by step development of a disease. The chain of events leading to that disease due to a series of changes in the structure and /or function of a cell/tissue/organ. Caused by a microbial, chemical or physical agent.

3. Pathogenicity - Ability to cause disease Virulence - Degree of pathogenicity Many properties that determine a microbe’s pathogenicity or virulence are unclear or unknown But, when a microbe overpowers the hosts defenses, disease results!

4. 3. Parentarel Microorganisms are deposited into the tissues below the skin or mucus membranes Punctures Injections Bites Scratches Surgery Splitting of skin due to swelling or dryness

5. Number of Invading Microbes LD 50 - Lethal Dose of a microbes toxin that will kill 50% of experimentally inoculated test animal ID 50 - infectious dose required to cause disease in 50% of inoculated test animals Example: ID 50 for Vibrio cholerea 10 8 cells (100,000,000 cells) ID 50 for Inhalation Anthrax - 5,000 to 10,000 spores

6. Steps involved in the pathogenesis of the bacteria: 1. Transmission/Entry 2. Colonization 3. Adhesion 4. Invasion 5. Survival in the host 6. Tissue Injury

7. Transmission/Entry Potential pathogens may enter the body by various routes, including the respiratory, gastrointestinal, urinary or genital tracts. Alternatively, they may directly enter tissues through insect bites or by accidental or surgical trauma to the skin. Many opportunistic pathogens are carried as part of the normal human flora, and this acts as a ready source of infection in the compromised host (e.g. in cases of AIDS or when the skin barrier is breached).

8. Transmission

9. Colonization The establishment of a stable population of bacteria on the host’s skin or mucous membranes is called colonization. For many pathogenic bacteria, the initial interaction with host tissues occurs at a mucosal surface and colonization normally requires adhesion to the mucosal cell surface. This allows the establishment of a focus of infection that may remain localized or may subsequently spread to other tissues

10. Adhesion Adhesion is necessary to avoid innate host defense mechanisms such as peristalsis in the gut and the flushing action of mucus, saliva and urine, which remove non-adherent bacteria. For bacteria, adhesion is an essential preliminary to colonization and then penetration through tissues. Successful colonization also requires that bacteria are able to acquire essential nutrients—in particular iron—for growth.

11. Adhesion At the molecular level, adhesion involves surface interactions between specific receptors on the mammalian cell membrane (usually carbohydrates) and ligands (usually proteins) on the bacterial surface. The presence or absence of specific receptors on mammalian cells contributes significantly to tissue specificity of infection.

12. Invasion Invasion is penetration of host cells and tissues (beyond the skin and mucous surfaces), and is mediated by a complex array of molecules, often described as ‘invasins’. These can be in the form of bacterial surface or secreted proteins which target host cell molecules (receptors).

13. Invasion Once attached to a mucosal surface, some bacteria, e.g. Corynebacterium diphtheriae or Clostridium tetani, exert their pathogenic effects without penetrating the tissues of the host. These produce biologically active molecules such as toxins, which mediate tissue damage at local or distant sites.

14. SURVIVAL IN THE HOST Many bacterial pathogens are able to resist the cytotoxic action of plasma and other body fluids involving antibody and complement (classical pathway) or complement alone (alternate pathway) or lysozyme. Killing of extracellular pathogens largely occurs within phagocytes after opsonization (by antibody and/ or complement) and phagocytosis.

15. Mechanisms of Survival Capsules (many pathogens), Protein A ( S. aureus) and M protein (S. pyogenes) function in this regard .

16. TISSUE INJURY Bacteria cause tissue injury primarily by several distinct mechanisms involving: Exotoxins Endotoxins and non-specific immunity Specific humoral and cell mediated immunity

17. How do Bacterial Pathogens penetrate Host Defenses? 1. Adherence - almost all pathogens have a means to attach to host tissue Binding Sites adhesins ligands

18. How Bacterial Pathogens Penetrate Host Defenses 1. Adherence 2. Capsule 3. Enzymes A. leukocidins B. Hemolysins C. Coagulase D. Kinases E. Hyaluronidase F. Collagenase G. Necrotizing Factor

19. Adhesins and ligands are usually on Fimbriae Neisseria gonorrhoeae ETEC (Entertoxigenic E. coli) Bordetella pertussis

20. 2. Capsules Prevent phagocytosis Attachment Streptococcus pneumoniae Klebsiella pneumoniae Haemophilus influenzae Bacillus anthracis Streptococcus mutans Yersinia pestis K. pneumoniae

21. 3. Enzymes Many pathogens secrete enzymes that contribute to their pathogenicity

22. A. Leukocidins Attack certain types of WBC’s 1. Kills WBC’s which prevents phagocytosis 2. Releases & ruptures lysosomes lysosomes - contain powerful hydrolytic enzymes which then cause more tissue damage

23. B. Hemolysins - cause the lysis of RBC’s Streptococci

24. 1. Alpha Hemolytic Streptococci - secrete hemolysins that cause the incomplete lysis or RBC’s

25. 2. Beta Hemolytic Streptococci - Secrete hemolysins that cause the complete lysis of RBC’s

26. C. Coagulase - cause blood to coagulate Blood clots protect bacteria from phagocytosis from WBC’s and other host defenses Staphylococci - are often coagulase positive boils abscesses

27. D. Kinases - enzymes that dissolve blood clots 1. Streptokinase - Streptococci 2. Staphylokinase - Staphylococci Helps to spread bacteria - Bacteremia Streptokinase - used to dissolve blood clots in the Heart (Heart Attacks due to obstructed coronary blood vessels)

28. E. Hyaluronidase Breaks down Hyaluronic acid (found in connective tissues) “Spreading Factor” Mixed with a drug to help spread the drug through a body tissue

29. F. Collagenase Breaks down collagen (found in many connective tissues) Clostridium perfringens - Gas Gangrene uses this to spread thru muscle tissue

30. G. Necrotizing Factor - Causes death (necrosis) to tissue cells “Flesh Eating Bacteria”

31. Bacterial Toxins Poisonous substances produced by microorganisms Toxins - primary factor - pathogenicity 220 known bacterial toxins 40% cause disease by damaging the Eukaryotic cell membrane Toxemia Toxins in the bloodstream

32. Types of Toxins 1. Exotoxins Exotoxins are generated by the bacteria and actively secreted Secreted outside the bacterial cell 2. Endotoxins Part of the outer cell wall of Gram (-) bacteria The body's response to endotoxin can involve severe inflammation.

33. Exotoxins Mostly seen in Gram (+) Bacteria Heat labile, can be inactivated by heating at 60-80 ۠ C. Excreted [ secreted] from the microbial cells into the surrounding ie culture media or circulatory system Don’t require bacterial death or cell lysis for their release.

34. Types of Exotoxins 1. Cytotoxins Kill cells- shigella, vibrio 2. Neurotoxins Interfere with normal nerve impulses Clostridium botulinum Clostridium tetani 3. Enterotoxins Effect cells lining the G.I. Tract E. coli Salmonella

35. Response to Toxins If exposed to exotoxins: antibodies against the toxin (antitoxins) Exotoxins inactivated ( heat, formalin or phenol) no longer cause disease, but stimulate the production of antitoxin altered exotoxins - Toxoids Toxoids - injected to stimulate the production of antitoxins and provide immunity

36. Endotoxins Part of the Gram (-) Bacterial cell wall. Biological activity or toxicity of endotoxin is largely due to lipid A. Relatively heat stable can withstand heat over 60 ۠ C for many hours. Released upon cell lysis or death. Less potent than exotoxins, active in large doses only. Pyrogenic often produce fever in hosts. Salmonella, Shigella, Escherichia, Neisseria.

37. Bacteriocin Bacteriocins were first discovered by A. Gratia in 1925. He called his first discovery a colicine because it killed E. coli. Bacteriocins are proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strain(s). They are typically considered to be narrow spectrum antibiotics, though this has been debated.

38. Medical significance Bacteriocins are of interest in medicine because they are made by non-pathogenic bacteria that normally colonize the human body. Loss of these harmless bacteria following antibiotic use may allow opportunistic pathogenic bacteria to invade the human body.