PATHOGENESIS_OF_BACTERIAL_INFECTION _MBChB _ 11-Sept-2024.pptx

General pathogenesis of bacterial infections

1. PATHOGENESIS OF BACTERIAL INFECTION Angol Denish Calmax

2. Pathogenesis: Is simply the mechanisms that lead to diseases. Is the development of morbid conditions or disease; more specifically the cellular events and reactions and other pathologic mechanisms occurring in the development of disease [1] The course of an illness or condition, from its origin to manifestation and outbreak [2] The pathologic, physiologic, or biochemical mechanism resulting in the development of a disease or morbid process [3] Pathogenesis Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. © 2003 by Saunders, an imprint of Elsevier, Inc. All rights reserved. Mosby's Dental Dictionary, 2nd edition. © 2008 Elsevier, Inc. All rights reserved. Medical Dictionary for the Health Professions and Nursing © Farlex 2012

3. Bacterial pathogenesis: is the process and mechanisms by which bacteria cause diseases in their target host, often at the cellular or molecular level The pathogenesis of bacterial infection includes the initiation of the infectious process and the mechanisms leading to the development of signs and symptoms of bacterial disease. The outcome of the interaction between bacteria and host is determined by characteristics that favour establishment of the bacteria within the host and their ability to damage the host as they are opposed by host defense mechanisms. Among the characterics of bacteria are adherence to host cells, invasiveness, toxigenity, and ability to evade the host´s imm u ne system. If the bacteria or immunological reactions injure the host sufficiently, disease becomes apparent. Bacterial Pathogenesis

4. Basic terms frequently used in describing aspects of pathogenesis: Disease and Infectious Disease Disease Any deviation from a condition of good health and well-being Health is the state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (WHO online) Infectious Disease A disease condition caused by the presence or growth of infectious microorganisms or parasites

5. Basic terms frequently used in describing aspects of pathogenesis : Infection : Multiplication of an infectious agent within the body Note: Multiplication of the bacteria that are part of normal flora of gastrointestinal tract, skin, etc, is generally not considered an infection On the other hand , multiplication of pathogenic bacteria ( e.g . Salmonella species ), even if the person is asymptomatic, is deemed an infection

6. Basic terms frequently used in describing aspects of pathogenesis : Pathogen : A microorganism capable of causing disease . Non-pathogen : A microorganism that does not cause disease . It may be part of the normal flora. Opportunistic pathogen : An agent capable of causing disease only when the host´s resistance is impaired ( e.g . the patient is immunocompromised). An agent capable of causing disease only when spread from the site with normal bacterial microflora to the sterile tissue or organ. Opportunistic infection: An infection caused by microorganisms that are commonly found in the host’s environment. This term is often used to refer to infections caused by organisms in the normal flora.

7. Pathogenicity and Virulence Pathogenicity The ability of a microbe to cause disease This term is often used to describe or compare species Virulence The degree of pathogenicity in a microorganism This term is often used to describe or compare strains within a species Basic terms frequently used in describing aspects of pathogenesis :

8. Basic terms frequently used in describing aspects of pathogenesis: Toxigenicity The ability of a microorganism to produce a toxin that contributes to the development of disease. Invasion (to invade) The process whereby bacteria, parasites, fungi and viruses ENTER the host cells or tissues and spread in the body.  Evasion (to evade) A strategy used by pathogenic organisms (or tumours ) to DODGE (AVOID/ELUDE/ EVADE) the host's immune response to maximize their probability of being transmitted to a fresh host (or to continue growing, respectively).

9. Acute infection vs. chronic infection Acute Infection An infection characterized by sudden onset, rapid progression, and often with severe symptoms. Usually within a short period Chronic Infection An infection characterized by delayed onset and slow progression Basic terms frequently used in describing aspects of pathogenesis:

10. Primary infection vs. secondary infection Primary Infection An infection that develops in an otherwise healthy individual Secondary Infection An infection that develops in an individual who is already infected with a different pathogen Basic terms frequently used in describing aspects of pathogenesis:

11. Localized infection vs. systemic infection Localized Infection An infection that is restricted to a specific location or region within the body of the host Systemic Infection An infection that has spread to several regions/organs or areas in the body of the host Basic terms frequently used in describing aspects of pathogenesis:

12. Clinical infection vs. subclinical infection Clinical Infection An infection with obvious observable or detectable symptoms Subclinical Infection An infection with few or no obvious symptoms Basic terms frequently used in describing aspects of pathogenesis:

13. The suffix “- emia ” A suffix means “presence of an infectious agent” (especially in blood) Bacteremia: Presence of infectious bacteria in the blood stream Viremia: : Presence of infectious virus in the blood stream Fungemia : Presence of infectious fungus in the blood stream Parasitemia : Presence of infectious parasite in the blood stream Septicemia: PRESENCE & MULTIPLICATION of an infectious agent ( Especially bactertia ) in the bloodstream etc. Basic terms frequently used in describing aspects of pathogenesis:

14. The suffix “- itis ” A suffix meaning “inflammation of” Examples: Pharyngitis: Inflammation of the pharynx Endocarditis: Inflammation of the heart chambers Gastroenteritis: Inflammation of the gastrointestinal tract Basic terms frequently used in describing aspects of pathogenesis:

15. Source: Kayser , Medical Microbiology © 2005 Thieme Page 11

16. Pathogenesis of bacterial infection Humans and animals have abundant normal micro flora. Most bacteria do not produce disease but achieve a balance with the host that ensures the survival, growth, and propagation of both the bacteria and the host. Sometimes bacteria that are clearly pathogens (e.g. Salmonella typhi ) are present, but infection remains latent or subclinical and the host is a "carrier" of the bacteria.

17. Potential bacterial contributors to the pathogenesis of infectious diseases: Adhesins. They facilitate adhesion to specific target cells. Invasins . They are responsible for active invasion of the cells of the microorganism. Impedins . These components disable host immune defenses in some cases. Aggressins . These substances include toxins and tissue- damaging enzymes. Modulins . Substances that induce excess cytokine production (i.e., lipopolysaccharides of Gram-negative bacteria, superantigens, murein fragments)

18. The infectio n process Infection indicates multiplication of microorganisms. Prior to multiplication, bacteria (in case of bacterial infection) must enter and establish themselves within the host The most frequent portals of entry are : -T he respiratory (mouth and nose) -G astrointestinal -U rogenital tracts Abnormal areas of mucous membranes and skin ( e.g. cuts, burns) are also frequent sites of entry.

19. The infectio n process Once in the body, bacteria must attach or adhere to host cells, usually epithelial cells. After the bacteria have established a primary site of infection, they multiply and spread. Infection can spread directly through tissues or via the lymphatic system to bloodstream. Bloodstream infection ( bacteremia ) can be transient or persistent Bacteremia allows bacteria to spread widely in the body and permits them to reach tissues particularly suitable for their multiplication.

20. The infectio n process As an example of the infectio n process, Streptococcus pneumoniae can be cultured from the nasopharynx of 5-40% of healthy people. Occasionally, Streptococcus pneumoniae strains from the nasopharynx are aspirated into the lungs. Infection develops in the terminal air space of the lungs in persons who do not have protective antibodies against that type of Streptococcus pneumoniae . Multiplication of Streptococcus pneumoniae strains and resultant inflammation lead to pneumonia. The strains then enter the lymphatics of the lung and move to the bloodstream.

21. The infectio n process As an example of the infectious process, Streptococcus pneumoniae can be cultured from the nasopharynx of 5-40% of healthy people. Between 10% and 20% of persons with Streptococcus pneumoniae pneumonia have bacteremia at the time the diagnosis of pneumonia is made. Once bacteremia occurs, Streptococcus pneumoniae strains can spread to their preferred secondary sites of infection (e.g. cerebrospinal fluid, heart valves, joint spaces). The major resulting complications of Streptococcus pneumoniae pneumonia include meningitis, endocarditis and septic arthritis.

22. Bacterial virulence factors Many factors determine the virulence of bacteria, or their ability to cause infection and disease

23. Toxins Toxins produced by bacteria are generally classified into two groups: Exotoxins : are those released or secreted from bacterial cells and may act at tissue sites distant from the sites of bacterial infection, adhesion, and growth Endotoxins : are cell associated structural components of the gram-negative bacterial envelope, which may be released from growing bacterial cells as blebs or from lysed cells NB: Bacterial toxins, both soluble and cell-associated, may be transported by blood and lymph and induce cytotoxic effects at tissue sites remote from the original site of infection

24. Endotoxins of gram-negative bacteria The endotoxins of gram-negative bacteria are derived from bacterial cell walls and are often liberated when the bacteria lyse. The substances are heat - stable and can be extracted ( e.g . with phenol - water ).

25. Pathophysiological effects of endotoxins are similar regardless of their bacterial origin Fever Leukopenia Hypotension Impaired organ perfusion and acidosis Activation of C3 and complement cascade Disseminated intravascular coagulation (DIC) Death

26. Exotoxins Many gram-positive and gram-negative bacteria produce exotoxins of considerable medical importance . Some of these toxins have had major role in world history ( e.g . toxin of Clostridium tetani ).

27. Diphtheria toxin (toxin of Corynebacterium diphtheriae ) Corynebacterium diphtheriae strains that carry a temperate bacteriophage with the structural gene for the toxin are toxigenic and produce diphtheria toxin. This native toxin is enzymatically degraded into two fragments: A and B, linked together by a disulfide bound. Both fragments are necessary for toxin activity.

28. Tetanospasmin (toxin of Clostridium tetani ) Clostridium tetani is an anaerobic gram-positive rod that is widespread in the environment. Clostridium tetani contaminates wounds, and the spores germinate in the anaerobic environment of the devitalized tissue. The vegetative forms of Clostridium tetani produce toxin tetanospasmin. T he released toxin has two peptides linked by disulfide bounds. Toxin reaches the central nervous system by retrograde transport along axons and through the systemic circulation. The toxin acts by blocking release of an inhibitory mediator in motor neuron synapses. The result is initially localized then generalized, muscle spasms. Extremely small amount of toxin can be lethal for humans.

29. Botulotoxin (toxin of Clostridium botulinum ) Clostridium botulinum is found in soil or water and may grow in foods if the environment is appropriately anaerobic . An exceedingly potent toxin (the most potent toxin known) is produced by Clostridium botulinum strains. It is heat-labile and is destroyed by sufficient heating. There are eight disctinct serological types of toxin. Types A, B and E are most commonly associated wih human disease. Toxin is absorbed from the gut and carried to motor nerves, where it blocks the release of acetylcholine at synapses and neuromuscular junctions. Muscle contraction does not occur, and paralysis results.

30. Toxins of Clostridium perfringens Spores of Clostridium perfringens are introduced into the wounds by contamination with soil or faeces. In the presence of necrotic tissue (an anaerobic environment), spores germinate and vegetative cells produce several different toxins. Many of these are necrotizing and hemolytic and favour the spread of gangrene: alpha toxin is a lecithinase that damages cell membranes theta toxin also has a necrotizing affect Etc.

31. Streptococcal erythrogenic toxin Some strains of hemolytic lysogenic streptococci produce a toxin that results in a punctate aculopapular erythematous rash, as in scarlet fewer. Production of erythrogenic toxin is under the genetic control of temperate bacteriophage. If the phage is lost, the streptococi cannot produce toxin.

32. Toxic shock syndrom e toxin - 1 (TSST-1) Some Staphylococcus aureus strains growing on mucous m embranes (e.g. on the vagina in association with menstruation), or in wounds, elaborate TSST-1. Although the toxin has been associated with toxic shock syndrome, the mechanism of action in unknown . The illness is characterized by : - shock - high fewer - a diffuse red rash that later desquamates, - multiple other organs systems are affected

33. Exotoxins associated with diarrheal diseases Vibrio cholerae toxin Staphylococcus aureus enterotoxin Other enterotoxins - enterotoxins are also produced by some strains of: Yersinia en t erocolitica Vibrio parahaemolyticus Aeromonas species

34. Enzymes Many species of bacteria produce enzymes that are not intrinsically toxic but play important role in the infectious process Collagenase : degrades collagen , the major protein of fibrous connective tissue , and promotes spread of infection in tissue . Coagulase : Staphylococcus aureus produce coagulase , which works in conjuction with serum factors to coagulate plasma. Coagulase contributes to the formation of fibrin walls around staphylococcal lesions , which helps them persist in tissues .

35. Enzymes Hyaluronidases : Enzymes that hydrolyze hyaluronic acid, a constituent of the ground substance of connective tissue. They are produced by many bacteria (e.g. staphylococci, streptococci and anaerobes) and aid in their spread through tissues. Streptokinase : Many hemolytic streptococci produce streptokinase (fibrinolysin), substance that activates a proteolytic enzyme of plasma. This enzyme, also called fibrinolysin, is then able to dissolve coagulated plasma and probably aids in the spread of streptococci through tissues. Streptokinase is used in treatment of acute myocardial infarction to dissolve fibrin clots.

36. Enzymes Hemolysins and leukocidins : Many bacteria produce substances that are cytolysins - they dissolve red blood cells (hemolysins) or kill tissue cells or leukocytes (leukocidins) Streptolysin O, for example , is produced by group A streptococci and is letal for mice and hemolytic for red blood cells from many animals .

37. Antiphagocytic factors Many bacterial pathogens are rapidly killed once they are ingested by polymorphonuclear cells or macrophages. Some pathogens evade phagocytosis or leukocyte microbidical mechanisms by adsorbing normal host componets to their surfaces. For example, Staphylococcus aureus has surface protein A, which binds to the Fc portion of IgG. Other pathogens have surface factors that impede phag o cytosis e.g. Streptococcus pneumoniae and many other bacteria have polysaccharide capsules.

38. Adherence factors Once bacteria enter the body of the host, they must adhere to cells of a tissue surface If they do not adhere, they would be swept away by mucus and other fluids that bathe the tissue surface Adherence (which is only one step in the infect i ous process) is followed by development of microcolonies and subsequent complex steps in the pathogenesis of infection

39. Adherence factors The interactions between bacteria and tissue cell surfaces in the adhesion process are complex . Several factors play important role: surface hydrophobicity binding molecules on bacteria and host cell receptor interaction Examples: Pili are adhesive hair-like organelles that protrude from the surface of bacteria. They are uses for both the attachment to host cell, and exchange of genetic materials during conjugation Fimbriae: are form of pilli strictly used for attachment to the host cell or are proteinaceous filamenteous projections on the bacterial cell surfaces used as adhesins to assist in binding of the bacteria to specific receptor on the host cell.

40. The principal mechanisms of innate immunity to extracellular bacteria are - i . Complement activation -ii. Phagocytosis -iii. Inflammatory response. Peptidoglycan (in Gram + bacteria): activates the alternative pathway of the complement system promoting formation of the C3 convertase LPS (in Gram - bacteria) also activates the alternative complement pathway in the absence of antibody. Bacteria that express mannose on their surface may bind mannose-binding lectin, thereby leading to complement activation by the lectin pathway. Innate Immunity to Extracellular Bacteria

41. One result of complement activation is opsonization and enhanced phagocytosis of the bacteria. In addition, the membrane attack complex lyses bacteria, especially Neisseria species, and complement by-products stimulate inflammatory responses by recruiting and activating leukocytes. Phagocytes use various surface receptors , including mannose receptors and scavenger receptors , to recognize extracellular bacteria Phagocytes also use Fc receptors and complement receptors to recognize appropriately opsonized bacteria. Toll-like receptors (TLRs) of phagocytes participate in the activation of the phagocytes

42. These various receptors promote the phagocytosis of the microbes and stimulate the microbicidal activities of the phagocytes In addition, activated phagocytes secrete cytokines, which induce leukocyte infiltration into sites of infection (inflammation). Injury to normal tissue is a pathologic side effect of inflammation. Cytokines also induce the systemic manifestations of infection, including fever and the synthesis of acute-phase protein

43. Immune Evasion by Extracellular Bacteria

44. The virulence of extracellular bacteria has been linked to: -Antiphagocytic mechanisms -Complement inhibition/inactivation of complement pdts Bacteria with polysaccharide-rich capsules resist phagocytosis (more virulent) Sialic acid residues of many gram-positive capsules & gram-negative bacteria inhibit complement activation by the alternative pathway The pilin genes of gonococci (also E.Coli ) undergo extensive gene conversion, where the progeny of one organism can produce up to 10^6 antigenically distinct pilin molecules Innate immune Evasion by Extracellular Bacteria

45. A characteristic of facultative intracellular bacteria is their ability to survive and even replicate within phagocytes Intracellular bacteria are inaccessible to circulating antibodies, therefore eliminated by cell mediated immunity The pathologic consequences of infection by many intracellular bacteria are due to the host response to these microbes. IMMUNITY TO INTRACELLULAR BACTERIA

46. IMMUNITY TO INTRACELLULAR BACTERIA

47. The innate immune response to intracellular bacteria is mainly mediated by of phagocytes and natural killer (NK) cells Phagocytes, initially neutrophils (later macrophages ), ingest and attempt to destroy these microbes, but they resist degradation Intracellular bacteria activate NK cells by: - inducing expression of NK cell-activating ligands on infected cells -stimulating dendritic cell and macrophage production of IL-12 Innate Immunity to Intracellular Bacteria

48. Then NK cells produce IFN- γ , which in turn activates macrophages & promotes killing of the phagocytosed bacteria Thus, NK cells provide an early defense against these microbes, before the development of adaptive immunity. Innate Immunity to Intracellular Bacteria

49. Innate immune Evasion by Intracellular Bacteria

50. Different intracellular bacteria have developed various strategies to resist elimination by phagocytes : - inhibiting phagolysosome fusion - escaping into the cytosol, thus hiding from the microbicidal mechanisms of lysosomes - directly scavenging or inactivating microbicidal substances such as reactive oxygen species NB; Resistance to phagocyte-mediated elimination is also the reason that tend to cause chronic infections, recurrence after apparent cure, and difficult in eradication. Innate Immune Evasion by Intracellular Bacteria

51. Humoral immunity is the principal protective immune response against extracellular bacteria, and it functions to block infection, eliminate tile microbes, and neutralize their toxins Antibody responses against extracellular bacteria are directed against cell wall antigens and secreted and cell-associated toxins, which may be polysaccharides or proteins. The effector mechanisms used by antibodies to combat these infections include: - neutralization -opsonisation -phagocytosis -activation of complement by the classical pathway Adaptive Immunity to Extracellular Bacteria

52. Neutralization is mediated IgG & IgA isotypes, opsonization by some subclasses of IgG Then complement activation by IgM and subclasses of IgG. CD4+ helper T cells are activated to produce cytokines The cytokines then stimulate Antibody production, Induce local inflammation, Enhance the phagocytic process by macrophages and neutrophils Microbicidal activities of macrophages and neutrophils -IFN- γ : activates macrophage activation -TNF and Iymphotoxin trigger inflammation. -IL-17 (by "Th17" cells) neutrophil -rich inflammation and defense against some bacterial infections (recent research) Adaptive Immunity to Extracellular Bacteria

53. The principal injurious consequences of host responses to extracellular bacteria - inflammation -septic shock. The some reactions of neutrophils and macrophages that function to eradicate the infection also cause tissue damage by local production of reactive oxygen species and lysosomal enzymes . These inflammatory reactions are usually self-limited and controlled Septic shock: is a syndrome characterized by circulatory collapse and disseminated intravascular coagulation. - This is a severe pathologic consequence of disseminated infection by gram-negative and some gram-positive bacteria. Injurious Effects of Immune Responses

54. The early phase of septic shock is caused by cytokines produced by macrophages that are activated by microbial components, particularly LPS. TNF is the principal cytokine mediator of septic shock, but IFN- γ and interleukin-12 (IL-12) may also contribute. In fact, serum levels of TNF are predictive of the outcome of severe gram-negative bacterial infections. This early burst of deadly amounts of cytokines is sometimes called a "cytokine storm." Injurious Effects of Immune Responses

55. Evasion of humoral immunity is by genetic variation of surface antigens. The pilin genes of gonococci (also E.Coli ) undergo extensive gene conversion, where the progeny of one organism can produce up to 10^ 6 antigenically distinct pilin molecules Haemophilus influenzae, changes in the production of glycosidases leading to chemical alterations in surface LPS and other polysaccharides , which enable the bacteria to evade humoral immune responses against these antigens Adaptive Immune Evasion by Extracellular Bacteria

56. A characteristic of facultative intracellular bacteria is their ability to survive and even replicate within phagocytes Intracellular bacteria are inaccessible to circulating antibodies, therefore eliminated by cell mediated immunity The pathologic consequences of infection by many intracellular bacteria are due to the host response to these microbes. Adaptive immunity to intracellular bacteria

57. IMMUNITY TO INTRACELLULAR BACTERIA

58. The major protective immune response against intracellular bacteria is T cell-mediated immunity Cell-mediated immunity consists of two types of reactions: -macrophage activation by the T cell-derived signals CD40 ligand and -IFN -y, which results in killing of phagocytosed microbes, and lysis of infected cells by cytotoxic T lymphocytes (CTLs) Both CD4+ T cells and CD8+ T cells respond to protein antigens of phagocytosed microbes (displayed as peptides associated with class II and class I MHC molecules, respectively. Adaptive Immunity to Intracellular Bacteria

59. CD4+ T cells differentiate into TH1 effectors under the influence of IL-12, which is produced by macrophages and dendritic cells The T cells express CD40 ligand and secrete IFN-y: -these stimuli activate macrophages (produce: reactive oxygen species, nitric oxide, & lysosomal enzymes) Phagocytosed bacteria stimulate CD8+ T cell responses (if bacterial antigens or the bacteria escape from phagosomes to the cytoplasm of infected cells) In the cytoplasm, the infection is eradicated by the killing of infected cells by CTLs. Adaptive Immunity to Intracellular Bacteria