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Chapter 16 Innate Immunity: Nonspecific Defenses of the Host Lectures prepared by Christine L. Case © 2013 Pearson Education, Inc. Lectures prepared by Christine L. Case Copyright © 2013 Pearson Education, Inc. 致病源進入體內的途徑 食入 眼睛 呼吸道 注射 皮膚 Copyright © 2013 Pearson Education, Inc. Lectures prepared by Christine L. Case Koch’s Postulates Koch's Postulates are used to prove the cause of an infectious disease. 1 Microorganisms are isolated from a diseased or dead animal. 2a The microorganisms are grown in pure culture. Colony 3 The microorganisms are injected into a healthy laboratory animal. 4 Disease is reproduced 2b The microorganisms are identified. in a laboratory animal. 5a The microorganisms are isolated from this animal and grown in pure culture. Figure 14.3 Koch’s Postulates: Understanding Disease. 5b Microorganisms are identified. The microorganism from the diseased host caused the same disease in a laboratory host. Lectures prepared by Christine L. Case Copyright © 2013 Pearson Education, Inc. 感染源危險群與生物安全等級之關係及其應用限制 危險群 1 2 3 4 感染源 與健康成年人之疾病無關 很少引起人類嚴重疾病， 而且通常有預防及治療的 方法 可引起人類嚴重或致死疾 病，可能有預防及治療之 方法 可引起人類嚴重或致死疾 病，但通常無預防及治療 之方法 Copyright © 2013 Pearson Education, Inc. 生物安全等級 應用限制 生物安全等級 1 （ BSL-1） 基礎教學，研究 生物安全等級 2 （ BSL-2） 基本健康服務；診 斷，研究 生物安全等級 3 （ BSL-3） 特別診斷，研究 生物安全等級 4 （ BSL-4） 危險的病原體研究 Lectures prepared by Christine L. Case Mechanisms of Pathogenicity When the balance between host and microbe is tipped in favor of the microbe, an infection or disease results. Learning these mechanisms of microbial pathogenicity is fundamental to understanding how pathogens are able to overcome the host’s defenses. H1N1 flu virus portals of entry Mucous membranes • Respiratory tract • Gastrointestinal tract • Genitourinary tract • Conjunctiva Skin Parenteral route Number of invading microbes penetration or evasion of host defenses Capsules Cell wall components Enzymes Antigenic variation Invasins Intracellular growth Adherence damage to host cells Siderophores Direct damage Toxins • Exotoxins • Endotoxins Lysogenic conversion Cytopathic effects portals of exit Generally the same as the portals of entry for a given microbe: • Mucous membranes • Skin • Parenteral route Mycobacterium intracellulare Clostridium tetani Micrographs are not shown to scale. Figure Microbial Mechanisms of Pathogenicity. Copyright ©15.9 2013 Pearson Education, Inc. Lectures prepared by Christine L. Case The Stages of a Disease Figure stages ofInc. a disease. Copyright14.5 © 2013The Pearson Education, Lectures prepared by Christine L. Case The Concept of Immunity Learning Objectives 16-1 Differentiate innate and adaptive immunity. 16-2 Define Toll-like receptors. © 2013 Pearson Education, Inc. The Concept of Immunity Susceptibility: lack of resistance to a disease Immunity: ability to ward off disease Innate immunity: defenses against any pathogen Adaptive immunity: immunity or resistance to a specific pathogen © 2013 Pearson Education, Inc. An Overview of the Body’s Defenses First line of defense • Intact skin • Mucous membranes and their secretions • Normal microbiota Second line of defense • Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances Third line of defense • Specialized lymphocytes: T cells and B cells • Antibodies Figure 16.1 An overview of the body’s defenses. ANIMATION Host Defenses: The Big Picture © 2013 Pearson Education, Inc. The Concept of Immunity Host Toll-like receptors (TLRs) attach to pathogen-associated molecular patterns (PAMPs) TLRs induce cytokines that regulate the intensity and duration of immune responses © 2013 Pearson Education, Inc. First Line of Defense: Skin and Mucous Membranes Learning Objectives 16-3 Describe the role of the skin and mucous membranes in innate immunity. 16-4 Differentiate physical from chemical factors, and list five examples of each. 16-5 Describe the role of normal microbiota in innate immunity. © 2013 Pearson Education, Inc. Physical Factors Skin Epidermis consists of tightly packed cells with Keratin, a protective protein Figure 16.2 A section through human skin. © 2013 Pearson Education, Inc. Physical Factors Mucous membranes Mucus: traps microbes Ciliary escalator: transports microbes trapped in mucus away from the lungs © 2013 Pearson Education, Inc. Ciliary Escalator Figure 24.7 Ciliated cells of the respiratory system infected with Bordetella pertussis. © 2013 Pearson Education, Inc. Ciliary Escalator Trapped particles in mucus Cilia Goblet cells Insert Fig 16.4 Ciliated cells Computer-enhanced Figure 16.4 The ciliary escalator. © 2013 Pearson Education, Inc. Physical Factors Lacrimal apparatus: washes eye Saliva: washes microbes off Urine: flows out Vaginal secretions: flow out © 2013 Pearson Education, Inc. Lacrimal Apparatus Lacrimal glands Upper eyelid Lacrimal canal Nasolacrimal duct Nose Figure 16.3 The lacrimal apparatus. © 2013 Pearson Education, Inc. Chemical Factors Fungistatic fatty acid in sebum Low pH (3–5) of skin Lysozyme in perspiration, tears, saliva, and urine Low pH (1.2–3.0) of gastric juice Low pH (3–5) of vaginal secretions © 2013 Pearson Education, Inc. Normal Microbiota and Innate Immunity Microbial antagonism/competitive exclusion: Normal microbiota compete with pathogens or alter the environment Commensal microbiota: One organism (microbe) benefits and the other (host) is unharmed May be opportunistic pathogens Normal microbiota protect the host by: occupying niches that pathogens might occupy producing acids producing bacteriocins © 2013 Pearson Education, Inc. Second Line of Defense Learning Objectives 16-6 Classify leukocytes, and describe the roles of granulocytes and monocytes. 16-7 Define differential white blood cell count. 16-8 Differentiate the lymphatic and blood circulatory systems. © 2013 Pearson Education, Inc. Formed Elements in Blood Insert Table 16.1 If possible, break into multiple slides © 2013 Pearson Education, Inc. Formed Elements in Blood Insert Table 16.1 If possible, break into multiple slides © 2013 Pearson Education, Inc. Differential White Cell Count Percentage of each type of white cell in a sample of 100 white blood cells Neutrophils 60–70% Basophils 0.5–1% Eosinophils 2–4% Monocytes 3–8% Lymphocytes 20–25% © 2013 Pearson Education, Inc. White Blood Cells Neutrophils: Phagocytic Basophils: Produce histamine Eosinophils: Toxic to parasites and some phagocytosis Dendritic cells: Initiate adaptive immune response Monocytes: Phagocytic as mature macrophages Lymphocytes: Involved in specific immunity. © 2013 Pearson Education, Inc. Components of Lymphatic System Thoracic (left lymphatic) duct Right lymphatic duct Right subclavian vein Left subclavian vein Tonsil Thymus Heart Thoracic duct Spleen Lymphatic vessel Small intestine Large intestine Peyer’s patch Lymph node Red bone marrow © 2013 Pearson Education, Inc. (a) Components of lymphatic system Figure 16.5a The lymphatic system. The Lymphatic System Venule Interstitial fluid Blood capillary Tissue cell Blood One-way opening Arteriole Blood Lymphatic capillary Interstitial fluid (between cells) Lymph Tissue cell Lymphatic capillary Relationship of lymphatic capillaries to tissue cells and blood capillaries Figure 16.5b-c The lymphatic system. ANIMATION Host Defenses: Overview © 2013 Pearson Education, Inc. Lymph Details of a lymphatic capillary Second Line of Defense Learning Objectives 16-9 Define phagocyte and phagocytosis. 16-10 Describe the process of phagocytosis, and include the stages of adherence and ingestion. 16-11 Identify six mechanisms of avoiding destruction by phagocytosis. © 2013 Pearson Education, Inc. Phagocytosis Phago: From Greek, meaning eat Cyte: From Greek, meaning cell Ingestion of microbes or particles by a cell, performed by phagocytes Figure 16.6 A macrophage engulfing rod-shaped bacteria. © 2013 Pearson Education, Inc. Phagocytosis Neutrophils Fixed macrophages: Fixed macrophages in lungs, liver, and bronchi Wandering macrophages: Wandering macrophages roam tissues © 2013 Pearson Education, Inc. Phagocytosis Pseudopods A phagocytic macrophage uses a pseudopod to engulf nearby bacteria. Phagocyte Cytoplasm 3 Formation of phagosome 1 CHEMOTAXIS 2 (phagocytic vesicle) INGESTION and of microbe by phagocyte ADHERENCE of phagocyte to microbe Microbe Lysosome or other particle Details of adherence PAMP (peptidogly can in cell wall) TLR (Toll-like receptor) ANIMATION Phagocytosis: Mechanism © 2013 Pearson Education, Inc. Digestive enzymes Partially digested microbe Indigestible material Figure 16.7 The Phases of Phagocytosis. 5 DIGESTION of ingested microbes by enzymes in the phagolysosome 6 Formation of the residual body containing indigestible material Plasma membrane ANIMATION Phagocytosis: Overview 4 Fusion of phagosome with a lysosome to form a phagolysosome 7 DISCHARGE of waste materials Oxidative Burst 4 Superoxide dismutase converts superoxide to hydrogen peroxide (H2O2) 5 H2O2 burst kills bacterium 3 NADPH oxidase 1 Bacterium adheres to membrane of neutrophil Insert art from Clinical Case on Superoxide p. 463 dismutase O2 • H2O2 Plasma membrane uses electron from NADPH to produce superoxide (O2 •) O2 If possible on this slide, include title: Oxidative Burst Neutrophil NADPH oxidase Pentose phosphate pathway NADP+ 2 NADPH is produced NADPH © 2013 Pearson Education, Inc. Microbial Evasion of Phagocytosis Inhibit adherence: M protein, capsules Streptococcus pyogenes, S. pneumoniae Kill phagocytes: Leukocidins Staphylococcus aureus Lyse phagocytes: Membrane attack complex Listeria monocytogenes Escape phagosome Shigella, Rickettsia Prevent phagosome– lysosome fusion HIV, Mycobacterium tuberculosis Survive in phagolysosome Coxiella burnettii ANIMATION Virulence Factors: Hiding from Host Defenses ANIMATION Virulence Factors: Inactivating Host Defenses ANIMATION Phagocytosis: Microbes that Evade It © 2013 Pearson Education, Inc. Second Line of Defense Learning Objectives 16-12 List the stages of inflammation. 16-13 Describe the roles of vasodilation, kinins, prostaglandins, and leukotrienes in inflammation. 16-14 Describe phagocyte migration. 16-15 Describe the cause and effects of fever. © 2013 Pearson Education, Inc. Inflammation Redness Swelling (edema) Pain Heat Acute-phase proteins activated (complement, cytokine, and kinins) Vasodilation (histamine, kinins, prostaglandins, and leukotrienes) Margination and emigration of WBCs Tissue repair © 2013 Pearson Education, Inc. Chemicals Released by Damaged Cells Histamine Kinins Vasodilation, increased permeability of blood vessels Vasodilation, increased permeability of blood vessels Prostaglandins Intensify histamine and kinin effect Leukotrienes Increased permeability of blood vessels, phagocytic attachment © 2013 Pearson Education, Inc. The Process of Inflammation © 2013 Pearson Education, Inc. Figure 16.8a-b The process of inflammation. Figure 16.8c The process of inflammation. Blood vessel endothelium Monocyte 4 Margination— phagocytes stick to endothelium. 5 Diapedesis— phagocytes squeeze between endothelial cells. Insert Fig 16.8c 6 Phagocytosis of invading bacteria occurs. Red blood cell Macrophage (c) Phagocyte migration and phagocytosis Bacterium Neutrophil © 2013 Pearson Education, Inc. Figure 16.8d The process of inflammation. Scab Blood clot Regenerated epidermis (parenchyma) Insert Fig 16.8d (d) Tissue repair Regenerated dermis (stroma) ANIMATION Inflammation: Overview ANIMATION Inflammation: Steps © 2013 Pearson Education, Inc. Fever Abnormally high body temperature Hypothalamus is normally set at 37°C Gram-negative endotoxins cause phagocytes to release interleukin-1 (IL-1) Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature Body increases rate of metabolism, and shivering occurs, which raise temperature Vasodilation and sweating: body temperature falls (crisis) © 2013 Pearson Education, Inc. Endotoxins and the Pyrogenic Response Figure 15.6 Endotoxins and the pyrogenic response. © 2013 Pearson Education, Inc. Fever Advantages Increases transferrins Increases IL-1 activity Produces interferon Disadvantages Tachycardia Acidosis Dehydration 44–46°C fatal © 2013 Pearson Education, Inc. Antimicrobial Substances Learning Objectives 16-16 List the major components of the complement system. 16-17 Describe three pathways of activating complement. 16-18 Describe three consequences of complement activation. © 2013 Pearson Education, Inc. The Complement System Serum proteins activated in a cascade Activated by Antigen–antibody reaction Proteins C3, B, D, P and a pathogen ANIMATION Complement: Overview ANIMATION Complement: Activation © 2013 Pearson Education, Inc. The Complement System C3b causes opsonization C3a + C5a cause inflammation C5b + C6 + C7 + C8 + C9 cause cell lysis ANIMATION Complement: Results © 2013 Pearson Education, Inc. The Complement System 1 Inactivated C3 splits into activated C3 C3a and C3b. 2 C3b binds to microbe, resulting in opsonization. C3b C3a C3b proteins 3 C3b also splits C5 into C5a and C5b 5 C3a and C5a cause mast cells to release histamine, resulting in inflammation; C5a also attracts phagocytes. opsonization C5 Enhancement of phagocytosis by coating with C3b C5a C5b C5a receptor Histamine C5a Insert Fig 16.9 Mast cell 4 C5b, C6, C7, and C8 bind together sequentially and insert into the microbial plasma membrane, where they function as a receptor to attract a C9 fragment; additional C9 fragments are added to form a channel. Together, C5b through C8 and the multiple C9 fragments form the membrane attack complex, resulting in cytolysis. C6 inflammation Increase of blood vessel permeability and chemotactic attraction of phagocytes C9 Microbial plasma membrane Channel C6 C5b C8 C9 Formation of membrane attack complex (MAC) © 2013 Pearson Education, Inc. C3a C8 C7 Figure 16.9 Outcomes of Complement Activation. C3a receptor C7 C6 C5b C7 C8 C9 Cytolysis cytolysis Bursting of microbe due to inflow of extracellular fluid through transmembrane channel formed by membrane attack complex Effects of Complement Activation Opsonization, or immune adherence: enhanced phagocytosis Membrane attack complex: cytolysis Attract phagocytes Figure 16.10 Cytolysis caused by complement. © 2013 Pearson Education, Inc. Inflammation Stimulated by Complement C5a C5a receptor Histamine Phagocytes Neutrophil Histaminecontaining granule Insert Fig 16.11 Histaminereleasing mast cell C3a C5a Macrophage C3a receptor Figure 16.11 Inflammation stimulated by complement. © 2013 Pearson Education, Inc. Classical Pathway of Complement Activation Microbe C1 is activated by binding to antigen–antibody complexes. Antigen Antibody C1 Activated C1 splits C2 into C2a and C2b, and C4 into C4a and C4b. C4 C2 Insert Fig 16.12 C2b C2a C2a and C4b combine and activate C3, splitting it into C3a and C3b (see also Figure 16.9). Opsonization C4b C3 C3b Figure 16.12 Classical pathway of complement activation. © 2013 Pearson Education, Inc. C4a Cytolysis C3a Inflammation Alternative Pathway of Complement Activation Lipid-carbohydrate complex Microbe C3 combines with factors B, D, and P on the surface of a microbe. B D P C3 This causes C3 to split into fragments C3a and C3b. Key: B B factor D D factor Insert Fig 16.13 P P factor C3a C3b Inflammation Opsonization © 2013 Pearson Education, Inc. Cytolysis Figure 16.13 Alternative pathway of complement activation. Lectin Pathway of Complement Activation Microbe Lectin Lectin binds to an invading cell. Bound lectin splits C2 into C2b and C2a and C4 into C4b and C4a. C2 C2b C4 C4b C2a C2a and C4b combine and activate C3 (see also Figure 16.9). Opsonization C4a C3 C3b C3a Cytolysis © 2013 Pearson Education, Inc. Carbohydrate containing mannose Figure 16.14 The lectin pathway of complement activation. Inflammation Some Bacteria Evade Complement Capsules prevent C activation Surface lipid–carbohydrate complexes prevent formation of membrane attack complex (MAC) Enzymatic digestion of C5a © 2013 Pearson Education, Inc. Antimicrobial Substances Learning Objectives 16-19 Define interferons. 16-20 Compare and contrast the actions of IFN-α and IFN-β with IFN-γ. 16-21 Describe the role of iron-binding proteins in innate immunity. 16-22 Describe the role of antimicrobial peptides in innate immunity. © 2013 Pearson Education, Inc. Interferons (IFNs) IFN-α and IFN-β: cause cells to produce antiviral proteins that inhibit viral replication IFN-γ: causes neutrophils and macrophages to phagocytize bacteria © 2013 Pearson Education, Inc. Antiviral Actions of Interferons (IFNs) 1 Viral RNA from an infecting virus enters the cell. 2 The infecting virus 5 New viruses released by the replicates into new viruses. Viral RNA virus-infected host cell infect neighboring host cells. 3 The infecting virus also induces the host cell to produce interferon mRNA (IFN-mRNA), which is translated into alpha and beta interferons. Infecting virus Viral RNA Nucleus Translation Insert Fig 16.15 Transcription Transcription IFN-mRNA 4 Interferons released by the virus-infected host cell bind to plasma membrane or nuclear membrane receptors on uninfected neighboring host cells, inducing them to synthesize antiviral proteins (AVPs). These include oligoadenylate synthetase and protein kinase. Alpha and beta interferons Translation Virus-infected host cell Figure 16.15 Antiviral action of alpha and beta interferons (IFNs). © 2013 Pearson Education, Inc. Neighboring host cell Antiviral proteins (AVPs) 6 AVPs degrade viral mRNA and inhibit protein synthesis—and thus interfere with viral replication. Innate Immunity Transferrins Bind serum iron © 2013 Pearson Education, Inc. Antimicrobial peptides Lyse bacterial cells
