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Phagocytosis and the Interactions of Various Phagocytes

Medical Microbiology. Phagocytosis and the Interactions of Various Phagocytes. BIOL 533 Lecture 6. Leukocyte Chemotaxins. Types of chemotaxins C5a attracts neutrophils and monocytes Made by bacteria

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Phagocytosis and the Interactions of Various Phagocytes

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  1. Medical Microbiology Phagocytosis and the Interactionsof Various Phagocytes BIOL 533 Lecture 6

  2. Leukocyte Chemotaxins • Types of chemotaxins • C5a attracts neutrophils and monocytes • Made by bacteria • Peptide clipped off N-terminus (beginning with N-formylmethionine) during peptide maturation after protein synthesis • Made by bacteria and nucleated blood cells • Leucotrienes—lipid products of cell membrane metabolism

  3. Leukocyte Chemotaxins • Function of chemotaxins • Enhance and direct motility of phagocytic cells • To a limited extent, oxidative metabolism of phagocytic cells

  4. Opsonization and Opsonins • General aspects • Substances that enhance ability of phagocytes to ingest microbes • Defend against presence of capsules and other microbial mechanisms that interfere with phagocytosis

  5. Opsonization and Opsonins • Types of opsonins • Antibodies • C3b component of complement • Binds covalently to bacterial surface and is recognized by receptors on neutrophils, monocytes, and macrophage • Bacteria become bound to surface of phagocyte facilitating their uptake

  6. Opsonization and Opsonins • Types of opsonins, continued • Mechanism • White blood cell receptors for C3b • At least 3—CR1, CR2, CR3 (complement receptor) • Children deficient in CR3 very vulnerable to bacterial infections

  7. Phagocytes—Types of Cells • Neutrophils—cell origin • Actively motile cells produced in bone marrow • Differentiate from stem cells over about a two-week period • Production of granules during this time • Azurophil • Produce specific granules later

  8. Phagocytes—Types of Cells • Neutrophils—cell origin, continued • Upon maturation (in numbers of 1010 per day), they move into peripheral blood and circulate for about 6.5 hours • Next move into capillary bed and marginate

  9. Phagocytes—Types of Cells • Neutrophils—cell origin, continued • Margination caused by stickiness due to interleukin-1 • Summoned by chemotaxis, they move through endothelial cell junctions (diapdesis) into extravascular tissue spaces

  10. Phagocytes—Types of Cells • Neutrophils are most active in gut • Gut has enormous microbial population lying just one cell layer away from aseptic tissue • Flora generates large amounts of chemotaxins that recruit most of body’s available leukocytes

  11. Phagocytes—Types of Cells • As a result, submucosa of gut is in a constant state of inflammation • Keep microbial flora down • Synthesis of neutrophils inhibited by chemicals or radiation • Infections in gut region

  12. Phagocytes—Types of Cells • Monocytes and macrophage • Compared to neutrophils • Arrive at damaged tissue later in infection • Days after neutrophils have been active in fighting intruders • Eventually settle in tissues and become resident macrophage

  13. Phagocytes—Types of Cells • Monocytes and macrophage • Share progenitor cell type, but kinetics of maturation & appearance are very different • Monocytes continue cell differentiation after leaving bone marrow • Monocytes and macrophage involved in both constititive and inducible mechanisms • Interact with T cells and play important role in cell-mediated immunity

  14. Phagocytes—Types of Cells • Tissue (resident) macrophage • Exist throughout body • Different names and functions in different tissues • Kupffer cells—liver • Alveolar macrophage—lungs • Osteoclasts—bone • Microglia—brain

  15. Phagocytes—Types of Cells • Monocyte and macrophage functions • Phagocytize invading microbes • Contribute greatly to inflammatory response • Releases • IL-1—enhances sticking of neutrophil to capillary endothelia • TNF—activates newly arrived neutrophils

  16. Mechanism of Phagocyte Killing • Neutrophils • General steps • Attach to microbes • Ingest microbes • Kill microbes • Granules—considered as enlarged lysosomes containing hydrolytic enzymes

  17. Mechanism of Phagocyte Killing • Neutrophil granule types • Azurophil (primary granule) • Contains • Lysozyme • Elastase • A chymotryptic-like protease • Myeloperoxidase • Several antibacterial cationic proteins

  18. Mechanism of Phagocyte Killing • Neutrophil granule types • Specific (secondary granule) • Contains • Cytochrome • Lysozyme • Lactoferin (iron-binding protein) • Vitamin B12 binding protein • Collagenase

  19. Mechanism of Phagocyte Killing • The neutrophil membrane • Contains receptors for chemotaxin and opsonins • After binding chemotaxins, receptors are internalized and replaced with new ones

  20. Mechanism of Phagocyte Killing • Effectiveness of chemotaxis: very effective • Neutrophils are very motile • Move by rearranging cytoplasmic microfilaments and microtubules • Actin and myosin in microfilaments are affected by protein gelsolin • Portions that face upstream in chemotactic gradient form structure called lamellipodium • Cytoplasm is densely packed with microfilaments • Portions face downstream form knob-like uropod

  21. Mechanism of Phagocyte Killing • Process of phagocytosis • General aspects • Differs from pinocytosis in that particles, not liquids, taken up

  22. Mechanism of Phagocyte Killing • Process of phagocytosis, continued • Receptors on phagocyte surface progressively attach to ligands on bacterial surface • Stimulates mechanisms of killing • Oxidative metabolism leading to production of hydrogen peroxide and compounds lethal to microbes (oxygen-dependent killing) • Discharge of toxic compounds from granules into phagosome (oxygen-independent killing)

  23. Mechanism of Phagocyte Killing • Process of phagocytosis, continued • Form phagosome—pouch-like structure that invaginates, displacing the nucleus and granules toward uropod • Form phagolysosome—membrane of granules and phagosome fuse, releasing toxic substances • Forms separate pinched-off organelle • Bacteria coated with antibacterial proteins

  24. Oxygen-Dependent Killing • Fusion of specific granules with phagosome membrane (derived from plasma membrane) brings together: • NADPH oxidase (oxidizes NADPH; found in neutrophil plasma membrane) • Unique cyt b (granule membrane) • A quinone

  25. Oxygen-Dependent Killing • Reaction • O2  O2— (reduces oxygen to superoxide radical) • 2O2—+ H2O  H2O2+ O2 (superoxide dismutase)

  26. Oxygen-Dependent Killing • Patients lacking cytochrome components • Children having chronic granulomatous disease (CGD) • Failure to synthesize superoxide radical and therefore hydrogen peroxide • Due to decreased amount of cytochrome b • Gene for larger subunit is missing (90K, 20K)

  27. Oxygen-Dependent Killing • Children having chronic CGD, cont’d. • Neutrophils can phagocytize normally, but do not efficiently oxidize NADPH and kill via oxidative pathway • Usually don’t survive into adulthood

  28. Oxygen-Dependent Killing • How does oxidative process kill? • Interaction with myeloperoxidase supplied by fusion with azurophil • Combines chloride ions and hydrogen peroxide to form hypochlorous ions (analogous to bleach) • Bacteria lacking catalase produce hydrogen peroxide (pneumococci); basically commit suicide • Pneumococci are not dangerous to CGD patients

  29. Oxygen-Independent Killing • Process • Triggered by binding opsonized bacteria to the plasma membrane of neutrophils • Specific granules fuse first • Deliver several bacteriodical proteins, including lysozyme and lactoferin

  30. Oxygen-Independent Killing • Azurophil granules discharge antimicrobial cationic proteins • Some are amphipathic and resemble other cationic surface proteins such as polymyxin B

  31. Oxygen-Independent Killing • Azurophil granules, continued • Disrupt outer membrane of Gram— and kill by causing leakage of vital components • Each of the proteins has unique antimicrobial spectrum, but tend to affect Gram— more than Gram+ • Proteins may account for survival of some CGD children

  32. Oxygen-Independent Killing • Efficiency • Bacterial killing under highly anaerobic conditions of deep abscesses • Patients lacking genes • Coding for cationic proteins • None found, maybe lethal

  33. Oxygen-Independent Killing • Chediak-Higashi syndrome (genetic disease) • Premature fusion of neutrophil granules while cells in bone marrow • When mature cells phagocytize, granules are already spent, substantially reducing killing power

  34. Comparison of Bacterial Sensitivity • Gram— rods in gut killed by oxygen-independent • Gram+ bacteria on skin and upper respiratory epithelia are resistant to oxygen-independent and killed by oxygen-dependent

  35. Mechanism of Phagocyte Killing • Eosinophils • Much like neutrophils, but indicative of parasitic infection

  36. Killing by Monocytes and Macrophage • General aspects • Tend to take care of what is left after battle with neutrophils • Mechanisms of chemotaxis, phagocytosis, and killing resemble mechanisms of neutrophils • Not studied in same detail

  37. Killing by Monocytes and Macrophage • Differences • Continue to differentiate after leaving bone marrow and are activated • Called “angry macrophage” • Phagocytize more vigorously • Take up more oxygen • Secrete large quantity of hydrolytic enzymes • In general, better prepared to kill

  38. Killing by Monocytes and Macrophage • Activated by • Elicited by substances made in response to presence of bacteria (C3b) or viruses (interferon) • Endotoxin of Gram— • Tetrapeptide derived from immunoglobulins (tuftsin)

  39. Killing by Monocytes and Macrophage • Microbial (bacterial, fungi, protozoa) growth within • Some can grow until activated, then killed • Participation in immune response • Help rid body of not only microbial invaders, but also tumor and foreign cells

  40. Killing by Monocytes and Macrophage • Immune response process • Stimulate development of T lymphocytes • Respond to signals from other lymphocytes that stimulate differentiation and activation of macrophage

  41. Phagocytotic Killing • Macrophages/neutrophils/mast cells stimulated by • TNF • interferon • Produce reactive nitrogen intermediates • Nitric oxide • Nitrite (NO2—) • Nitrate (NO3—)

  42. Phagocytotic Killing • Released from cells or contained within vacuoles • Macrophages produce NO from arginine when stimulated by cytokines • NO can block cellular respiration by complexing iron in electron transport proteins

  43. Macrophage Killing • Herpes simplex • Toxoplasma gondii • Leishmania major • Cryptococcus neoformans • Schistosoma mansoni

  44. Lecture 6 • Questions? • Comments? • Assignments...

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