Fat2.chapter15 (pathogenicity)

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MICROBIAL MECHANISM OF PATHOGENICITY

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Fat2.chapter15 (pathogenicity)

  1. 1. Chapter 15 Microbial Mechanisms of Pathogenicity
  2. 2. Microbial Mechanisms of Pathogenicity <ul><li>Pathogenicity The ability to cause disease </li></ul><ul><li>Virulence The extent of pathogenicity </li></ul><ul><li>~when a microbe overpowers the hosts defenses, disease results ~ </li></ul><ul><li>They need to gain entry , adhere , penetrate and cause damage to cause disease. </li></ul>
  3. 3. Disease: Pathogens may cause damage to host <ul><li>Direct damage in the immediate vicinity </li></ul><ul><ul><li>Grow and multiply and clog cells and passageways </li></ul></ul><ul><li>Far removed from site of invasion by toxins </li></ul><ul><ul><li>Toxins spread through blood and lymph </li></ul></ul><ul><li>By hypersensitivity </li></ul><ul><ul><li>The host’s reaction may cause the damage </li></ul></ul>
  4. 4. <ul><li>Portals of Entry </li></ul><ul><li>Mucous membranes </li></ul><ul><ul><li>Respiratory tract </li></ul></ul><ul><ul><li>Gastrointestinal tract </li></ul></ul><ul><ul><li>Genitourinary tract </li></ul></ul><ul><ul><li>Conjunctiva </li></ul></ul><ul><li>Skin </li></ul><ul><ul><li>Tough so rare - Necator americanus - hookworm </li></ul></ul><ul><li>Parenteral route </li></ul><ul><ul><li>Puncture, injection, bites, cuts, wounds, surgery, etc </li></ul></ul>How microorganisms enter a host?
  5. 5. 1 st Portal of Entry :Mucous Membranes -Respiratory <ul><li>Respiratory Tract </li></ul><ul><ul><li>microbes inhaled into mouth or nose in droplets of moisture or dust particles </li></ul></ul><ul><ul><li>Easiest and most frequently traveled portal of entry </li></ul></ul><ul><li>Common cold </li></ul><ul><li>Flu </li></ul><ul><li>Tuberculosis </li></ul><ul><li>Whooping cough </li></ul><ul><li>Pneumonia </li></ul><ul><li>Measles </li></ul><ul><li>Strep Throat </li></ul><ul><li>Diphtheria </li></ul>
  6. 6. Mucous membranes: G.I. Tract <ul><li>Salmonellosis </li></ul><ul><ul><li>Salmonella sp. </li></ul></ul><ul><li>Shigellosis </li></ul><ul><ul><li>Shigella sp. </li></ul></ul><ul><li>Cholera </li></ul><ul><ul><li>Vibrio cholorea </li></ul></ul><ul><li>Ulcers </li></ul><ul><ul><li>Helicobacter pylori </li></ul></ul><ul><li>Botulism </li></ul><ul><ul><li>Clostridium botulinum </li></ul></ul><ul><li>Fecal - Oral Diseases </li></ul><ul><li>These pathogens enter the G.I. Tract at one end and exit at the other end. </li></ul><ul><li>Spread by contaminated hands & fingers or contaminated food & water </li></ul><ul><li>Poor personal hygiene. </li></ul>
  7. 7. Mucous Membranes of the Genitourinary System - STD’s <ul><li>Gonorrhea </li></ul><ul><li>Neisseria gonorrhoeae </li></ul><ul><li>Syphilis </li></ul><ul><li>Treponema pallidum </li></ul><ul><li>Chlamydia </li></ul><ul><li>Chlamydia trachomatis </li></ul><ul><li>HIV </li></ul><ul><li>Herpes Simplex II </li></ul>
  8. 8. Mucous Membranes: Conjunctiva <ul><li>Conjunctiva </li></ul><ul><ul><li>mucous membranes that cover the eyeball and lines the eyelid </li></ul></ul><ul><li>Trachoma --------------  </li></ul><ul><ul><li>Chlamydia trachomatis </li></ul></ul>
  9. 9. 2nd Portal of Entry: Skin <ul><li>Skin - the largest organ of the body . When unbroken is an effective barrier for most microorganisms. </li></ul><ul><li>Some microbes can gain entrance thru openings in the skin: hair follicles and sweat glands </li></ul>
  10. 10. 3rd Portal of Entry: Parenteral <ul><li>Microorganisms are deposited into the tissues below the skin or mucous membranes </li></ul><ul><ul><li>Punctures </li></ul></ul><ul><ul><li>injections </li></ul></ul><ul><ul><li>bites </li></ul></ul><ul><ul><li>scratches </li></ul></ul><ul><ul><li>surgery </li></ul></ul><ul><ul><li>splitting of skin due to swelling or dryness </li></ul></ul>
  11. 11. Preferred Portal of Entry <ul><li>~ Just because a pathogen enters your body it does not mean it’s going to cause disease ~ </li></ul><ul><li>Pathogens - preferred portal of entry </li></ul><ul><ul><li>Small pox via variolation </li></ul></ul><ul><ul><li>Streptococcus pneumoniae </li></ul></ul><ul><ul><ul><li>if inhaled can cause pneumonia </li></ul></ul></ul><ul><ul><ul><li>if enters the G.I. Tract, no disease </li></ul></ul></ul><ul><ul><li>Salmonella typhi </li></ul></ul><ul><ul><ul><li>if enters the G.I. Tract can cause Typhoid Fever </li></ul></ul></ul><ul><ul><ul><li>if on skin, no disease </li></ul></ul></ul>
  12. 12. <ul><li>ID 50 : Infectious dose for 50% of the test population </li></ul><ul><li>- virulence of pathogens </li></ul><ul><li>LD 50 : Lethal dose (of a toxin) for 50% of the test population </li></ul><ul><li>- potency of toxin </li></ul>Numbers of Invading Microbes ~ the probability of disease increases as the number of pathogens increases ~
  13. 13. ID 50 for Bacillus anthracis 250,000-1,000,000 endospores Ingestion 10,000-20,000 endospores Inhalation 10 - 50 endospores Skin ID 50 Portal of entry
  14. 14. Key traits to a pathogen <ul><li>The ability to: </li></ul><ul><li>1. Adherence </li></ul><ul><ul><li>To host surfaces and not be washed off </li></ul></ul><ul><li>2. Avoid phagocytosis </li></ul><ul><ul><li>Prevent host defenses from destroying </li></ul></ul><ul><li>3. Penetrate </li></ul><ul><ul><li>Get into host and spread </li></ul></ul><ul><li>4. Produce Enzymes </li></ul><ul><ul><li>Spread, prevent host defenses and cause damage at or near site of infection </li></ul></ul><ul><li>5. Produce Toxins </li></ul><ul><ul><li>Cause damage at distant site </li></ul></ul>
  15. 15. <ul><li>Adhesins or ligands </li></ul><ul><ul><li>– surface molecules on the pathogen that binds specifically to complementary surface RECEPTORS of host cells. </li></ul></ul><ul><ul><li>- located in glycocalyx, pili, fimbrae, flagella </li></ul></ul><ul><ul><li>Biofilms – another method of adherence </li></ul></ul><ul><ul><li>- communities which constitute masses of microbes & their extracellular products that can attach to living & nonliving surfaces </li></ul></ul><ul><ul><li>Examples: </li></ul></ul><ul><ul><li>> dental plaque of teeth </li></ul></ul><ul><ul><li>> algae on walls of swimming pools </li></ul></ul><ul><ul><li>> scum on shower walls </li></ul></ul>Adherence
  16. 16. Mechanisms of adhesion of some pathogens: <ul><li>Streptococcus mutans , a major cause of tooth decay, attaches to the surface of the teeth by means of its glycocalyx. Next,  Actinomyces  uses its fimbriae to attach to the glycocalyx of  S. mutans . (biofilm) </li></ul><ul><li>Pathogenic strains of  Escherichia coli   have adhesins or fimbriae that adhere to cells in certain regions of the small intestine.  E. coli  and  Shigella  cause host cells to take them in by endocytosis and then multiply inside them.  </li></ul><ul><li>Treponema pallidum   hooks its tapered end into a host cell. </li></ul><ul><li>Listeria monocytogenes  produces an adhesin for specific receptors on host cells. </li></ul><ul><li>Neisseria gonorrhoeae  also has fimbriae with adhesins which fit receptors of cells in the genitourinary tract, eyes, and pharynx. </li></ul><ul><li>Staphylococcus aureus  binds to skin cells in a mechanism similar to that of viruses. </li></ul>
  17. 17. Adherence
  18. 18. How bacterial pathogens penetrate host defenses? <ul><li>Factors contribute to the ability of bacteria to invade a host: </li></ul><ul><ul><li>Capsules </li></ul></ul><ul><ul><li>Enzymes </li></ul></ul><ul><ul><li>Antigenic variation </li></ul></ul><ul><ul><li>Penetration into the host cell cytoskeleton </li></ul></ul>
  19. 19. Capsules <ul><li>Resist the host’s defenses by impairing phagocytosis </li></ul><ul><li>Chemical substances of capsules that contribute to virulence: </li></ul><ul><li>M protein – heat resistant & acid-resistant protein </li></ul><ul><ul><ul><li>- mediates attachment of bacterium to epithelial cells of the host & helps bacterium resist phagocytosis by white blood cells </li></ul></ul></ul><ul><li>ex. Streptococcus pyogenes </li></ul><ul><li>Opa – outer membrane protein; together with fimbrae attach to host cells </li></ul><ul><ul><li>ex. Neisseria gonorrhea – grows in human epithelial cells & leukocytes </li></ul></ul><ul><li>Waxes – resist digestion by phagocytes </li></ul><ul><li>ex. e x . Mycobacterium tuberculosis </li></ul>
  20. 20. <ul><ul><li>Increase virulence by use of enzymes </li></ul></ul><ul><ul><li>And avoid phagocytosis </li></ul></ul><ul><ul><li>Bacterial Enzymes </li></ul></ul><ul><ul><li>Coagulase Coagulate the fibrinogen in blood </li></ul></ul><ul><ul><li>Kinases Break down fibrin and dissolve blood clots formed by the body to isolate infection </li></ul></ul><ul><ul><li>streptokinase and staphylolinase </li></ul></ul><ul><ul><li>Hyaluronidase Breaks down polysaccharide that </li></ul></ul><ul><ul><li>holds together connective tissue </li></ul></ul><ul><ul><li>Collagenase Hydrolyzes protein collagen </li></ul></ul><ul><ul><li>IgA proteases Destroy IgA antibodies </li></ul></ul><ul><ul><li>Hemolysins Lyses RBC’s </li></ul></ul>Enzymes
  21. 21. Antigenic Variation <ul><li>Process in which a pathogen alter their surface antigens to avoid host antibodies </li></ul><ul><li>Examples: </li></ul><ul><li>> N. gonorrhea ( have copies of the Opa-encoding genes, resulting in cells with different antigens and in cells that express different antigens over time.) </li></ul><ul><li>> Influenzavirus - flu </li></ul><ul><li>> Trypanosoma brucie gambiense – sleeping sickness </li></ul>
  22. 22. Penetration into the Host Cell Figure 15.2
  23. 23. Penetration into the Host Cell Cytoskeleton <ul><li>Microbes attach by adhesions </li></ul><ul><li>Triggers signals in host cell that activates factors that results in the entry of some bacteria </li></ul><ul><li>Bacteria produce invasions, which rearrange actin </li></ul><ul><li>Causes cytoskeleton disruption </li></ul><ul><li>Allows bacteria to enter </li></ul>
  24. 24. How Bacterial Pathogens Damage Host Cells? <ul><li>If pathogen overcomes host defenses then microorganism can damage host cells by: </li></ul><ul><ul><li>Using host cell nutrients </li></ul></ul><ul><ul><li>Causing direct damage </li></ul></ul><ul><ul><li>Inducing hypersensitivity reactions </li></ul></ul><ul><ul><li>Producing toxins </li></ul></ul>
  25. 25. Using the Host’s Nutrients <ul><li>Bacteria require iron </li></ul><ul><li>Most iron in body tightly bound to iron-transport proteins </li></ul><ul><li>Some bacteria produce siderophores (a protein) - take iron away from iron-transport proteins </li></ul>
  26. 26. Direct Damage <ul><li>Use host cell for nutrients and produce waste products </li></ul><ul><li>As pathogens metabolize and multiply in cells, cells usually rupture </li></ul><ul><li>Then move onto other cells </li></ul>
  27. 27. Production of Toxins <ul><li>Terminology: </li></ul><ul><li>Toxin - Poisonous substances that contribute to pathogenicity </li></ul><ul><ul><ul><ul><ul><li>- transported by blood or lymph </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- inhibit protein synthesis, destroy red blood cells, disrupt nervous system </li></ul></ul></ul></ul></ul><ul><li>Toxigenicity - ability to produce a toxin </li></ul><ul><li>Toxemia - presence of toxin the host's blood </li></ul><ul><li>Toxoid - inactivated toxin used in a vaccine </li></ul><ul><li>Antitoxin - antibodies against a specific toxin </li></ul>
  28. 28. Types of Toxins (based on their position relative to microbial cell) <ul><li>Endotoxins from inside the cell. Released upon cell lysis. </li></ul><ul><li>Exotoxins are secreted out of the cell during cell life </li></ul>
  29. 29. Exotoxins Figure 15.4a <ul><li>Produced inside some bacteria as part of growth and metabolism and then secreted </li></ul><ul><li>Diffuse easily within blood and rapidly travel throughout body </li></ul><ul><li>Destroy parts of host cells or inhibit metabolic functions </li></ul>
  30. 30. Three Principal Types of Exotoxin: <ul><li>A-B toxins ( type III toxin ) </li></ul><ul><li>> designated A & B parts which are both polypeptides. </li></ul><ul><li>>A- part, active (enzyme) components </li></ul><ul><li>>B-part, binding component </li></ul><ul><li>Membrane-disrupting Toxins ( type II Toxin ) </li></ul><ul><ul><li>>cause lysis of host cells by disrupting plasma membrane through forming protein channels in plasma membrane & disrupting phospholipid portion of plasma membrane </li></ul></ul><ul><li>Superantigens ( type I toxin ) </li></ul><ul><li>> bacterial protein that provoke very strong immune response </li></ul>
  31. 31. The action of an exotoxin (A-B toxin) ~diptheria toxin~
  32. 32. Membrane-disrupting toxins -Hemolysins <ul><li>Alpha Hemolytic Streptococci </li></ul><ul><li>secrete hemolysins that cause the incomplete lysis or RBC’s </li></ul><ul><li>Beta Hemolytic Streptococci </li></ul><ul><li>- secrete hemolysins that cause the complete lysis of RBC’s </li></ul>
  33. 33. Membrane-disrupting toxins - Leukocidins <ul><li>Enzymes that attack certain types of WBC’s </li></ul><ul><li>1. Kills WBC’s which prevents phagocytosis </li></ul><ul><li>2. Releases & ruptures lysosomes </li></ul><ul><ul><li>lysosomes - contain powerful hydrolytic enzymes which then cause more tissue damage </li></ul></ul>
  34. 34. Exotoxins (based on the host cell they attached): <ul><li>neurotoxins – attack nerve cells </li></ul><ul><li>cardiotoxins – attack heart cells </li></ul><ul><li>hepatotoxins – attack liver cells </li></ul><ul><li>leukotoxins – attack leukocytes </li></ul><ul><li>enterotoxins – attack the lining of the gastrointestinal tract </li></ul><ul><li>cytotoxins – attack wide variety of cells </li></ul>
  35. 35. Notable Exotoxins <ul><li>Diptheria Toxin ( Corynebacterium diptheriae) </li></ul><ul><li>Erythrogenic Toxin (Strpetoccocus pyogenes) </li></ul><ul><li>Botulinum Toxin (Clostridium botulinum) </li></ul><ul><li>Tetanus Toxin (Clostridium tetani) </li></ul><ul><li>Vibrio enterotoxin (Vibrio cholerae) </li></ul><ul><li>Staphylococcus enterotoxin ( Styphylococcus aureus) </li></ul>
  36. 36. Exotoxins Superantigen. Type I. Enterotoxin. • Staphylococcus aureus + A-B toxin. Enterotoxin. Stimulates cAMP to cause severe diarrhea • Vibrio cholerae A-B toxin. Neurotoxin - prevents CNS inhibition - spastic paralysis • C. tetani + A-B toxin. Neurotoxin - flaccid paralysis Botox • Clostridium botulinum + Membrane-disrupting. Type II Erythrogenic. • Streptococcus pyogenes + A-B toxin type III. Inhibits protein synthesis. • Corynebacterium diphtheriae Lysogenic conversion Exotoxin
  37. 37. Endotoxin Figure 15.4b <ul><li>part of outer membrane of G -bacteria </li></ul><ul><li>endotoxins released when G - bacteria die </li></ul><ul><li>exert affect by stimulating macrophages to release cytokines at very high levels </li></ul><ul><li>The lipid portion of the lipopolysaccharide, called lipid A, is the endotoxin. Endotoxins are lipopolysaccharides instead of proteins. </li></ul><ul><li>stimulate macrophages to release excess amounts of cytokines resulting to chills, fever, weakness, aching, and in extreme cases shock and even death </li></ul><ul><li>contribute to miscarriages </li></ul><ul><li>activate blood-clotting proteins, causing the formation of many small blood clots that block capillaries. Tissues thus deprived of their blood supply die. This is called disseminated intravascular clotting (DIC). </li></ul>
  38. 38. <ul><li>Septic shock - Shock caused by bacteria </li></ul><ul><ul><ul><ul><li>a severe drop in blood pressure. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Following phagocytosis and lysis of the gram-negative bacteria, the phagocytic cell secretes a polypeptide called tumor necrosis factor (TNF) or cachectin. This substance binds to many body tissues and alters their metabolism. One effect is damage to capillaries that increases their permeability and causes them to leak fluid, thus lowering blood pressure and leading to shock. The lowered blood pressure is also harmful to kidneys, lungs, and the digestive tract. </li></ul></ul></ul></ul>
  39. 39. <ul><li>Hemophilus influenzae  type b (G – bacteria) in cerebrospinal fluid cause the release of both IL-1 and TNF, which weaken the protective blood-brain barrier and allow bacteria to enter the CNS. Septic shock is very dangerous—up to 50% of cases may be fatal. </li></ul><ul><li>Organisms that produce endotoxins include: </li></ul><ul><li>    1.  Salmonella typhi  (typhoid fever) </li></ul><ul><li>    2.  Proteus  (frequent cause of urinary tract infections) </li></ul><ul><li>    3.  Neisseria meningitidis  (meningococcal meningitis) </li></ul>
  40. 40. <ul><li>If bacteria have grown and produced endotoxins in material that is later sterilized, the endotoxins retain their potency even though no living bacteria are still present. A test called the Limulus  amoebocyte lysate (LAL) can be used to detect even traces of endotoxin. </li></ul>
  41. 41. Endotoxins & the pyrogenic response: Figure 15.6
  42. 42. PLASMIDS, LYSOGENY, AND PATHOGENICITY   <ul><li>Plasmids - small circular pieces of DNA that are not part of the main bacterial chromosome and contain genes not found on the main chromosome </li></ul><ul><li>- replicated and passed on to daughter cells during cell division. </li></ul><ul><li>- may contribute to bacterial pathogenicity, often by carrying genes for making toxins. </li></ul><ul><li>- with the plasmid, the bacteria cause additional harm to the host. </li></ul>
  43. 43. <ul><li>Lysogeny – a state in which bacteriophages incorporate their DNA into the bacterial chromosome ,thus, becoming a prophage. </li></ul><ul><ul><li>Lysogenic cells - cells containing the prophage. </li></ul></ul><ul><li>Lysogenic conversion - genes carried on the phage DNA may give lysogenic cells new characteristics. </li></ul><ul><li>Toxins produced due to genes of prophages: </li></ul><ul><li>      Diphtheria toxin </li></ul><ul><li>      Erythrogenic toxin </li></ul><ul><li>      Staphylococcal enterotoxin </li></ul><ul><li>      Pyrogenic toxin </li></ul><ul><li>      Botulinum neurotoxin </li></ul><ul><li>      Capsule of  Streptococcus pneumoniae  (not exactly a toxin but contributes to virulence) </li></ul><ul><li>      Vibrio toxin </li></ul>
  44. 44. Mechanisms of Pathogenicity Figure 15.9

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