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Chapter 23, 24, 26 Lecture Outline Human Microflora, Nonspecific and Specific Host Defenses, and Immunizations Human Microbiota Humans colonized by many microbes Bacteria, archaea, fungi, protzoa, and viruses Normal flora “Commensal” (mutualistic) organisms Resident Transient Microbe populations change constantly Vary with type of tissue, condition pH, moisture, other microbes present Intestinal flora varies with nutrient uptake Can cause disease if reach abnormal location or if epithelial defense is impaired 2 Distribution of Microbiota Gram+ GramGram+ Gram- Gram+ Gram- Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 3 Body Site Lead Bacteria Skin Staphylococcus spec. Nose/pharynx Neisseria, viridans streptococci Stomach Sparsely populated Small intestine Bifidobacterium spec., Clostridium spec. Large intestine Bacteroides spec., E. coli Vagina Lactobacillus spec. Urethra Mycobacterium spec. Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 4 Human Microbiota: Skin Skin is difficult to colonize Dry, salty, acidic, protective oils Gram+ tolerate salt and dry environment well 1012 microbes in moist areas Scalp, ears, armpits, genital and anal areas Disease involvement: Propionibacterium acnes degrades skin oil Free fatty acid induce inflammation Inflamed sebaceous glands Causes acne Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 5 Human Microflora: Nose, Mouth Nasopharynx and Oropharynx Many Gram+ Also Gram Staphylococcus species Streptococcus species Neisseria spec. Fusobacterium spec. Disease involvement: Viridans streptococci can enter bloodstream and cause endocarditis Streptococcus mutans Can form biofilm around teeth Plaque Cause of gum disease Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 6 Viridans Streptococci S. mutans Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 7 Human Microbiota: Stomach Very high acidity Few microbes survive Disease involvement Helicobacter pylori Survive at pH 1 Burrow into protective mucous Cause of ulcers, cancer Loss of acidity = achlorhydria Caused by malnourishment Allows pathogen growth Example: Vibrio cholerae survive Pass through stomach Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 8 Human Microbiota: Intestine Vast majority of human microbiota 109-11 cells/ cm3 Feces consists primarily of bacteria Disease development Urinary tract infection Microbiology: An Evolving Science Sepsis © 2009 W. W. Norton & Company, Inc. 9 Human Genitourinary Microbiota Kidney and bladder are sterile Urethra and vagina are populated Vagina Acidic secretions prevent pathogens Lactobacillus acidophilus in vagina Composition is influenced by hormonal cycle Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 10 Important Contributions of Human Microbiota to Human Health Production of antimicrobials hampers colonization by pathogenic microbes Degradation of nutrients Vitamin production Modulation of immune system Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 11 Probiotics Oral uptake of microbes to the benefit of human health Gram-positive bacteria Must be able to survive stomach and small intestine Lactobacillus Bifidobacterium Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 12 Risks of Microbiota Opportunistic pathogens Surface breach allows bacterial entry Immunocompromised hosts E.g., Bacteroides fragilis E.g., Clostridium difficile Gas gangrene caused by Bacteroides after intestinal surgery Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 13 Host Defenses General mechanism Innate Immunity Adaptive immunity Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 14 General Host Defenses Physical barriers to infection Skin Mucous Keratin Dead skin cells, washing, remove attached cells Trap, destroy pathogens Mucous layers slough off, removed Cilia remove microbes from lungs Chemical barriers to infection Acidic pH: stomach, skin, vagina Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 15 Overview of the Immune System Innate immunity Widely present in nature Natural immunity Defense system functional at birth Preformed or available within hours after infection Pattern recognition Adaptive immunity In higher vertebrates Acquired Available within days Specificity Memory Proliferation and clonal expansion 16 Key Molecules of Our Immune System Antimicrobial peptides and polypeptides Natural peptide antibiotics Make pores in microbial membranes Lysozyme Complement Peptidoglycan hydrolase Can make membrane pores too Innate Immunity Makes pores in microbial membranes Enhances phagocytosis Alerts the host Antibodies Neutralize Block Enhance phagocytosis Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. Adaptive Immunity 17 Key Cells of Our Immune System Epithelial cells Leukocytes White blood cells Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 18 Epithelial Cells Innate immune system Line all body surfaces Equipped with receptors that recognize microbial products (Toll-like receptors, TLRs) LPS Peptidoglycan Produce antimicrobial peptides Produce cytokines that alert the host Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 19 Epithelial Cell Defense Microbial Products (LPS, PG, etc) TLR Antimicrobial Peptides TLR: Toll-like receptor (pattern recognition) LPS: lipopolysaccharide PG: peptidoglycan Cytokines Leukocytes Neutrophils and monocytes Engulf and destroy bacteria and fungi Innate Immunity Basophils and eosinophils granules with toxin Eliminate virus infected cells Lymphocytes Adaptive Immunity Release toxins to poison parasites Natural killer cells Monocytes are immature cells that eventually differentiate into macrophages and dendritic cells T cells: modulate specific immune response (T helper cells) and kill infected host cells (cytotoxic T cells) B cells: produce antibodies to bind foreign antigens 21 Main Steps of Phagocytosis Adhesion Engulfment (ingestion) Phagosome formation Phagolysosome formation Killing Digestion Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 22 Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 23 Acute Inflammatory Response Initial lesion Microbial specific structures activate epithelial cells and attract nearby phagocytes Cytokines from Phagocytes epithelial cells and engulf microbes. local phagoctes make capillaries permeable and attract neutrophils Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. Microbes are killed, wound heals, and return to normal. 24 Fever Pyrogens induce temperature rise Exogenous pyrogens LPS Cause release of endogenous pyrogens Endogenous pyrogens Cytokines Signal brain to raise temperature High temperature stresses invading microbes Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 25 Innate Defense by Interferon Type 1 interferons produced by infected host cells Cells with viral or bacterial pathogens Secrete small interferon proteins Nearby cells respond to interferons Causes recipient cells to resist virus Synthesizes ds RNA endonuclease Makes proteins to prevent protein translation from viral RNA Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 26 Adaptive Immunity Humoral immunity Mediated by antibodies Involves B cells that respond to specific antigens and produce specific antibodies Cellular immunity Involves T cells Special subtypes T helper cells control antibody production, activate innate immune cells Cytotoxic T cells (killer cells) directly kill infected host cells Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 27 Immunological Memory Mediated by Lymphocytes Specific antigen recognition + Memory m m Clonal proliferation m m m m m Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 28 Basic Structure of Antibodies Made by B lymphocytes (Immunoglobulins) 2 light chains 2 heavy chains Connected by disulfide bridges Antigen binding region Amino acids in this region are highly variable Each B cell makes a unique antibody Effector region Interact with host cells Amino acids in this region are highly constant 5 different classes (M, G, A,E,D) B cell can switch Ig classes 29 Antibody Isotypes have Different Functions IgM—First antibody in immune response IgG—Primary circulating antibody in blood Forms pentamer, agglutinates Coats antigen, eases engulfment by phagocytes (opsonization) IgA—Secreted across mucosa IgE—bound by mast cells and basophils and plays role in allergic responses IgD—on surface of B cells and maturation marker Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 30 Antibody Response Primary antigen exposure Disease or vaccination Antibodies appear in serum after several days B cells that bind antigen make antibodies IgM, then switch to IgG—Isotype switching B cells change to memory cells Secondary exposure to antigen Pathogen or booster dose Antibodies appear in blood within hours Mostly IgG antibodies Microbiology: An Evolving Science Some new IgM are also formed © 2009 W. W. Norton & Company, Inc. 31 Natural and Artificial Immunity Natural Course of natural infection Antigen is in its natural form Toxin (active) Microbe (replicative) Artificial Vaccination and immunizations Antigen is modified Inactivated Ex: Toxoid Attenuated Live vaccine but unable to cause the disease Never give to pregnant and immunocompromised individuals Ex: BCG vaccine Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 32 Active and Passive Immunizations Active Antigen (active, inactivated or attenuated) is introduced into host Passive Natural infection Vaccination Host mounts immune response Antibodies T cell mediated immunity Long-term protection Host must be immunocompetent Functional specific immune mediators are introduced into the host Antibodies Ex: maternal antibody transfer in utero Host does not mount an immune response No long-term protection For immediate protection Host can be immunocompromised Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 33 Vaccines Most vaccines administered in childhood Most administered as multiple booster doses Except influenza—new vaccine every year Herd immunity Protects from person-to-person transmission If 70% of community is immune Vaccinated or recovered from disease Remaining individuals protected Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 34