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Prescott’s Microbiology, 9th Edition 33 Innate Host Resistance CHAPTER OVERVIEW Humans resist parasitic relationships by employing both nonspecific and specific mechanisms. The nonspecific resistance mechanisms are explored in this chapter. Physical barriers of innate resistance are discussed for several tissues and organs. The details of innate immunity are presented, including complement activation, cytokines, and acute phase proteins. There is a discussion of immunity and the cells and organs involved in human immune responses. The mechanisms of cellular immunity are presented and inflammation detailed. LEARNING OUTCOMES After reading this chapter you should be able to: • • • • • • • • • • • • • • • • • • • • identify the major components of the mammalian host immune system integrate the major immune components and their functions to explain in general terms how the immune system protects the host identify the barriers that help prevent microbial invasion of the host explain how the physical and mechanical barriers function to prevent microbial invasion of the host relate host anatomy and secretions to the success of innate resistance strategies discuss host mediators that have antimicrobial actions describe in general terms the activation of the host complement system and its three outcomes list the three categories of cytokines and discuss their major functions correlate host protection from microbial invasion with specific mediators recognize the different types of leukocytes involved with innate resistance outline the leukocyte response to microbial invasion integrate leukocyte distribution within the host with host resistance differentiate between primary and secondary lymphoid organs and tissues in terms of structure and function predict connections between innate host resistance and specific immune responses explain the methods by which pathogens are recognized by phagocytes describe the processes of autophagy and phagocytosis forecast how biochemical activities within the phagocyte result in pathogen destruction outline the sequence of innate host responses that result in inflammation distinguish acute and chronic inflammation in terms of the host responses involved in each construct a concept map relating host cells and processes that remove pathogens CHAPTER OUTLINE I. Innate Resistance Overview A. To establish infection, a pathogen must first overcome barrier defenses B. If a pathogen succeeds, the immune system offers protection 1. The immune system is composed of widely distributed cells, tissues, and organs that recognize foreign materials and microorganisms C. Immunity—ability of a host to resist a particular disease; immunology—the science that deals with immune responses 1. Two types of immune responses a. Nonspecific immune responses (also called innate or natural immunity) 1) General resistance mechanisms inherited as part of the innate structure and function of each animal 2) Lack immunological memory 3) Nonspecific response occurs to same extent with each encounter 1 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part. Prescott’s Microbiology, 9th Edition b. Specific immune response (also called acquired, adaptive, or specific immunity) 1) Resists a particular foreign agent by an immune response (e.g., production of antibodies) to specific antigens 2) Improves on repeated exposure c. Multiple bridges occur between innate and adaptive immunity; a variety of white blood cells function in both systems II. Physical and Mechanical Barrier Defenses of Innate Resistance A. Many factors influence host-microbe relationships (e.g., nutrition, age, genetic factors, hygiene) B. Physical and mechanical barriers 1. Skin—provides a very effective mechanical barrier to microbial invasion, due to its thick, closely packed cells, frequent shedding and by being acidic and salty 2. Mucous membranes—mucus secretions form a protective covering that contains antibacterial substances, such as lysozyme, lactoferrin, and lactoperoxidase 3. Respiratory system a. Aerodynamic filtration deposits organisms onto mucosal surfaces, and microbes become entrapped in mucus (mucociliary blanket) b. Activity of ciliated epithelial cells transports microbes away from the lungs (mucociliary escalator); coughing, sneezing, and salivation also remove microorganisms c. Alveolar macrophages destroy those pathogens that get to the alveoli 4. Gastrointestinal tract a. Gastric acid kills most microorganisms b. In intestines, pancreatic enzymes, bile, intestinal enzymes, GALT, peristalsis, normal microbiota, lysozyme (produced by Paneth cells), and antibacterial peptides (cryptins) destroy or remove microorganisms 5. Genitourinary tract a. Kidneys, ureters, and urinary bladder are sterile due to multiple factors (e.g., pH and flushing action) b. Vagina produces glycogen, which is fermented by lactobacilli to lactic acid, thus lowering the pH and inhibiting other organisms III. Chemical Mediators in Innate Resistance A. Gastric juices, salivary glycoproteins, lysozyme, oleic acid on the skin, urea, and other chemicals have already been discussed B. Antimicrobial peptides 1. Cationic peptides damage bacterial plasma membranes through electrostatic interactions a. Cathelicidin—one of a group of linear alpha-helical peptides (12 to 80 amino acids) produced by a variety of cells (e.g., neutrophils, respiratory epithelia) b. Defensins—a diverse group of disulfide-linked, open-ended peptides (29 to 42 amino acids) found in a variety of cells (e.g., neutrophils, Paneth cells) c. Histatins—larger peptides with regular structural repeats 2. Bacteriocins—plasmid-encoded antibacterial peptides produced by normal bacterial flora; are lethal to related species through a variety of mechanisms C. Complement 1. The complement system is a set of serum proteins that play a major role in the immune response; complement has three major physiological activities: defending against bacterial infections, bridging innate and adaptive immunity, and disposing of wastes 2. During opsonization, the microorganism is coated with antibodies, mannan-binding protein, and/or complement proteins (together known as opsonins); this promotes recognition and phagocytosis 3. Complement acts in a cascade fashion; the complement proteins are produced in an inactive form, and the activation of one (by cleavage of the protein) leads to the sequential activation of others 4. There are three pathways of complement activation a. Alternative complement pathway—occurs in response to intravascular invasion by bacteria and some fungi; involves interaction of complement with the surface of the pathogen forming the membrane attack complex 2 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part. Prescott’s Microbiology, 9th Edition b. Lectin complement pathway (also called the mannan-binding lectin pathway)—occurs when macrophages stimulate liver cells to release acute phase proteins such as mannosebinding protein (a lectin), which then can activate complement via the alternative pathway or the classical pathway c. Classical pathway—results from antigen-antibody interactions that occur during specific immune responses 5. Complement action a. Membrane attack complexes can create a pore in the microbial cell membrane which uncouples gradients and leaves cells susceptible. b. Inflammatory action- complement fragments stimulate factors which allow inflammation which leads to vessel permeability and attraction of neutrophils D. Cytokines 1. Cytokines are soluble proteins or glycoproteins that are released by one cell population and act as intercellular mediators a. Monokines—released from mononuclear phagocytes b. Lymphokines—released from T lymphocytes c. Interleukins—released from a leukocyte and act on another leukocyte d. Colony-stimulating factors (CSFs)—stimulate growth and differentiation of immature leukocytes in the bone marrow 2. Cytokines can affect various cell populations a. Autocrine function—affect the same cell responsible for its production b. Paracrine function—affect nearby cells c. Endocrine function—distributed by circulatory system to target cells 3. Exert their effects by binding to cell-surface receptors called cell-association differentiation antigens (CDs); possible effects include: a. Stimulation of cell division b. Stimulation of cell differentiation c. Inhibition of cell division d. Apoptosis—programmed cell death e. Stimulation of chemotaxis and chemokinesis 4. Interferons (INFs)—Regulatory cytokines produced by certain eukaryotic cells in response to viral infection; in addition to protecting against viral infections, interferons also help regulate the immune response 5. Fever—results from disturbances in hypothalamic regulatory control, leading to increase of thermal “set point” a. Most common cause of fever is viral or bacterial infection, usually due to action of an endogenous pyrogen (e.g., interleukin-1, interleukin-6, tissue necrosis factor), which induces secretion of prostaglandins; these reset the hypothalamic thermostat b. Fever augments host’s defenses three ways 1) Stimulates leukocytes so that they can destroy the microorganism 2) Enhances specific activity of the immune system 3) Enhances microbiostasis (growth inhibition) by decreasing available iron to the microorganisms 6. Acute phase proteins—produced by liver in response to cytokines; act as opsonins and activate complement; collectins act as molecular scavengers that bind cellular debris IV. Cells, Tissues, and Organs of the Immune System A. Cells of the immune system 1. Leukocytes—white blood cells; arise from pluripotent stem cells in bone marrow and migrate to other body sites to mature and perform their functions; include all the cells described below a. Respond to pathogen-associated molecular patterns (PAMPS) to recognize microbes b. Receptors to PAMPS are known as pattern recognition receptors (PRRs) 2. Mast cells—found in connective tissue; contain granules with histamine and other chemicals that contribute to immune response; play important role in allergies and hypersensitivities 3. Granulocytes—also called polymorphonuclear neutrophils (PMNs) 3 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part. Prescott’s Microbiology, 9th Edition a. B. Basophils—nonphagocytic; upon stimulation, release chemicals (e.g., histamine, prostaglandins) that impact blood vessels (vasoactive); basophils play important roles in allergic responses b. Eosinophils—mobile cells that migrate from bloodstream into tissue spaces; protect against protozoa and helminth parasites; also may have role in allergic responses c. Neutrophils—highly phagocytic cells that rapidly migrate to sites of tissue damage and infection 4. Monocytes, macrophages and dendritic cells—highly phagocytic cells a. Monocytes—mononuclear phagocytic cells that circulate in blood for short time and can migrate to tissues where they mature into macrophages b. Macrophages—larger than monocytes; have more organelles and possess receptors that allow them to discriminate self from nonself; surface molecules recognize common components of pathogens (pathogen-associated molecular patterns) and enable pattern recognition receptors; respond to opsonization (chemical enhancement of phagocytosis) c. Dendritic cells—phagocytose microorganisms and kill viruses by secreting interferon-α; mature dendritic cells migrate to blood stream or lymphatic system where they interact with B cells and natural killer cells and present foreign antigens to T cells 5. Lymphocytes a. Major cells of specific immune system; when activated can differentiate to stimulate the immune response, produce antibodies, or produce memory cells b. Divided into three populations: T cells, B cells, and natural killer cells (NK cells) c. B lymphocytes (or B cells) mature in bone marrow and disperse throughout lymphoid tissue; when activated, differentiate into plasma cells and produce antibodies d. T lymphocytes (or T cells) mature in thymus gland and circulate in blood or lymphoid tissue; when activated, T cells do not produce antibodies, but stimulate the immune response by producing cytokine proteins e. Natural killer cells are large, nonphagocytic, granular lymphocytes that destroy malignant cells and cells infected with microorganisms f. NK cell recognize and target in two ways: 1) Antibody-dependent cell-mediated cytotoxicity (ADCC)—receptors on NK cells link them to antibody-coated target cells 2) If NK cells bind class I major histocompatibility (MHC) molecule (a self antigen) on a cell's surface, killing is inhibited; if there is no class I MHC on the target cell (i.e., because cell is infected with virus or is malignant), then killing occurs through pore-forming proteins and cytotoxic enzymes (granzymes) Organs and tissues of the immune system 1. Primary lymphoid organs and tissues a. Thymus—site of T cell maturation b. Bone marrow—site of B-cell maturation in mammals c. Bursa of Fabricius—site of B-cell maturation in birds (origin of term B cell) 2. Secondary lymphoid organs and tissue a. Spleen—filters blood and traps blood-borne microorganisms and antigens; contains macrophages and dendritic cells that present antigens to T cells b. Lymph nodes—filter lymph and trap microorganisms and antigens; contain macrophages and dendritic cells that present antigens to T cells; T cells release cytokines that stimulate differentiation and proliferation of B cells in antibody-producing plasma cells and memory cells c. Some lymphoid tissue is closely associated with certain tissues d. SALT—skin-associated lymphoid tissue 1) Langerhans cells—specialized dendritic cells that phagocytose antigens, then migrate to lymph nodes and differentiate into interdigitating dendritic cells, a type of antigen-presenting cell; activate T cells, which interact with activated B cells to induce a humoral response 2) Intraepidermal lymphocytes—function as T cells to destroy antigen e. MALT—mucosal-associated lymphoid tissue 1) Several types, including gut-associated (GALT) and bronchial-associated (BALT) 4 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part. Prescott’s Microbiology, 9th Edition 2) MALT operates by the action of M cells in the mucous membrane; M cells phagocytose antigen and transport it either to a pocket within the M cell containing B cells and macrophages or to lymphoid follicles containing B cells V. Phagocytosis A. Phagocytic cells (monocytes, tissue macrophages, dendritic cells, and neutrophils) phagocytose infecting organisms; phagocytosis is the process by which invaders are recognized, ingested, and killed. Autophagy can occur to combat intracellular parasites B. Recognition of foreignness of the pathogen can be opsonin-dependent or opsonin-independent 1. Opsonin-independent recognition (nonopsonic)—uses nonspecific and specific receptors (pattern recognition receptors, PRRs) on the phagocytic cells to recognize and bind structures on the microorganism, or to signal the induction of host defense pathways a. Multilectin protein found on dendritic cells and macrophages uses recognition based on the interaction of surface lectins on one cell and surface carbohydrates on the pathogen b. Recognition based on the detection of conserved molecular structures that occur in patterns and are essential products of normal microbial physiology (pathogen-associated molecular patterns – PAMPs; e.g., LPS) 2. NOD-like receptors (NLRs) — cytoplasmic soluble PRR that recognizes nucleotide binding and oligomerization domains. Interacts with inflammasome 3. Toll-like receptors (TLRs) —PRRs act exclusively as signaling receptors that bind PAMPs and communicate with the cell nucleus to elicit the appropriate response to different classes of pathogens C. Intracellular digestion—ingested microorganism is enclosed in phagosome, which then fuses with lysosome; digestion occurs in phagolysosome 1. Lysosomal enzymes (e.g., lysozyme, phospholipase, proteases) hydrolyze microbial structural molecules 2. Lysosomes of macrophages and neutrophils have enzymes that make toxic reactive oxygen intermediates (e.g., superoxide radical) during the respiratory burst that accompanies phagocytosis 3. Macrophages, neutrophils, and mast cells form reactive nitrogen species (e.g., nitric oxide, nitrite and nitrate) that are potent cytotoxic agents 4. Neutrophil granules contain microbiocidal substances (e.g., defensins), which are delivered to the phagolysosome D. Exocytosis—the antigenic remains of invaders can be expelled from the cell (as neutrophils do) or further processed for antigen presentation on the lymphocyte cell surface (as macrophages and dendritic cells do) VI. Inflammation A. Nonspecific response to tissue injury characterized by redness, heat, pain, swelling, and altered function of the tissue B. Inflammatory response 1. Injured tissue cells release chemical signals (chemokines) that activate cells in capillaries 2. Interaction of selectins on vascular endothelial surface and integrins on neutrophil surface promotes neutrophil extravasation 3. Neutrophils attack pathogen 4. More neutrophils and other leukocytes are attracted to site of tissue damage to help destroy microorganisms C. Numerous inflammatory mediators function in response 1. Kallikrein—an enzyme that catalyzes formation of bradykinin 2. Bradykinin a. Binds capillary walls, causing movement of fluid and leukocytes into tissue and production of prostaglandins (cause pain) b. Binds mast cells, causing release of histamine and other inflammation mediators 3. Histamine—promotes movement of more fluid, leukocytes, bradykinin, and kallikrein into tissue D. During acute inflammation, pathogen is neutralized and eliminated by a series of events 1. Increase in blood flow and capillary dilation bring more antimicrobial factors and leukocytes into the area; these destroy the pathogen; dead cells also release antimicrobial factors 5 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part. Prescott’s Microbiology, 9th Edition 2. 3. 4. E. The rise in temperature stimulates the inflammatory response and may inhibit microbial growth A fibrin clot often forms and may limit the spread of the invaders so that they remain localized Phagocytes collect in the inflamed area and phagocytose the pathogen; chemicals stimulate release of neutrophils and increase the rate of granulocyte production Chronic inflammation is characterized by its longer duration, dense infiltration of lymphocytes and macrophages, and formation of granulomas (in some cases) CRITICAL THINKING 1. The skin is constantly being exposed to pathogenic organisms. However, it is a very effective barrier against infection—it is not easily colonized and it is not readily penetrated. Discuss the various properties of the skin that make it such an effective barrier against colonization and penetration. 2. Inflammation is an important nonspecific defense in response to tissue injury. Describe the steps involved in the inflammation response. Contrast acute and chronic inflammation. 3. The lumen of the gastrointestinal tract is effectively exposed to the outside world and in many places along the way the tract is separated by only a single layer of epithelial tissue. What mechanisms are in place to protect this portal of entry from potential pathogens? 4. The evolution of the immune system is a tale of co-evolution between host and pathogen. Some infectious microbes have evolved the ability to evade complement or become complement resistant. What modifications to microbes have developed to confer complement resistance? CONCEPT MAPPING CHALLENGE Use the following words to construct a concept map by providing your own linking words Phagocytosis Opsonin Mucous membrane Defensins Cytokines Bone marrow Physical barriers MAC Neutrophils Lymphocyte Leukocytes Macrophages Dendritic cells Cytokines Lymphoid tissue Complement system Opsonization Skin Endogenous pyrogen SALT Interferons GALT MALT T cells B cells Thymus Basophils Histamine 6 © 2014 by McGraw-Hill Education. This is proprietary material solely for authorized instructor use. Not authorized for sale or distribution in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part.