Lecture 19 Host Defense Against Infection

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Lecture 19Host Defense Against Infection

• Innate immunity
• Adaptive Immunity

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Response to Initial Infection
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Stages of Response to Infection
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Course of Typical Acute Infection
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Innate Host Defense Mechanisms

• Anatomic Factors
• Mechanical Factors
• Biochemical Factors

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Skin

• Stratified and cornified epithelium provides a
  mechanical barrier
• Indigenous microbiota competes with pathogens
• Acid pH inhibits growth of disease producing
  bacteria
• Bactericidal long chain fatty acids in sebaceous
  gland secretions

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Respiratory Tract

• Upper Respiratory Tract
• Nasal hairs induce turbulence
• Mucous secretions trap particles
• Mucous stream to the base of tongue where
  material is swallowed
• Nasal secretions contain antimicrobial substances
• Upper respiratory tract contains large resident
  flora
• Lower Respiratory Tract
• Particles trapped on mucous membranes of bronchi
  and bronchioles
• Beating action of cilia causes mucociliary
  stream to flow up into the pharynx where it is
  swallowed
• 90 of particles removed this way. Only smallest
  particles (lt10µ in diameter) reach alveoli
• Alveoli
• Alveolar macrophage rapidly phagocytize small
  particles

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Alimentary Tract

• General defense mechanisms
• Mucous secretions
• Integrity of of mucosal epithelium
• Peristaltic motions of the gut propel contents
  downward
• Secretory antibody and phagocytic cells
• Stomach
• Generally sterile due to low pH
• Small Intestine
• Upper portion contains few bacteria
• As distal end of ilieum is reached flora
  increases
• Colon
• Enormous numbers of microorganisms
• 50-60 of fecal dry weight is bacteria

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Genitourinary Tract

• Male
• No bacteria above urethrovesicular junction
• Frequent flushing action of urine
• Bactericidal substances from prostatic fluid
• pH of urine
• Bladder mucosal cells may be phagocytic
• Urinary sIgA
• Female (Vagina)
• Large microbial population (lactobacilli)
• Microorganisms produce low pH due to breakdown of
  glycogen produced by mucosal cells

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Eye

• Flushing action of tears which drain through the
  lacrimal duct and deposit bacteria in nasopharynx
• Tears contain a high concentration of lysozyme
  (effective against gram positive microorganisms

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Innate Immune Recognition

• All multicellular organisms are able to recognize
  and eliminate pathogens
• Despite their extreme heterogeneity, pathogens
  share highly conserved molecules, called
  pathogen-associated molecular patterns (PAMPs)
• Host cells do not share PAMPs with pathogens
• PAMPs are recognized by innate immune recognition
  receptors called pattern-recognition
  molecules/receptors (PRMs/PRRs)

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Three Functional Classes of PRRs/PRMs

• Endocytic receptors
• Macrophage mannose receptor
• Macrophage scavenger receptor (SR)
• Integrin CD11bCD18
• Secreted proteins
• Mannose-binding protein/lectin
• Pulmonary surfactant proteins A and D
• C-reactive protein (CRP)
• Signaling receptors
• Toll receptor family

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Endogenous Signals Induced by PAMPs

• Mediate inflammatory cytokines
• Interleukin-1 (IL-1)
• IL-6
• Tumor necrosis factor (TNF-a)
• Type 1 interferon (INF-I)
• Major effector cytokines
• Chemokines
• Antigen-presenting cells recognize PAMPs
• Same APC processes pathogens into specific
  pathogen-derived antigens and presents them with
  MHC encoded receptors to T-cells
• T-cell responds only when presented with both
  signals
• Different Effector Cytokines in Response to
  Different Pathogens (Th1 vs. Th2)

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Antimicrobial Peptides/Defensins

• Four hundred peptides described to date
• Defensins (3- 5-kD, four families in eukaryotes)
• a-defensins (neutrophils and intestinal Paneth
  cells)
• b-defensins (epithelial cells)
• Insect defensins
• Plant defensins
• Defensins appear to act by binding to outer
  membrane of bacteria, resulting in increased
  membrane permeability.
• May also play a role in inflammation and wound
  repair

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Complement System

• Three pathways now known
• Classical
• Alternative
• Lectin or MBL pathway (binding to
  mannose-containing carbohydrates)
• Host cells have complement regulatory proteins on
  their surface that protect them from spontaneous
  activation of C3 molecules

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Inflammatory Mediators in Innate Immunity

• Cytokines secreted by phagocytes in response to
  infection include
• IL-1
• activates vascular endothelium and lymphocytes
• Increases adhesiveness of leukocytes
• IL-6
• Induces B-cell terminal maturation into
  Ig-producing plasma cells
• IL-8
• Induces expression of b2 integrin adhesion
  molecules on neutrophils, leading to neutrophil
  migration to infection site
• IL-12
• Activates NK cells and induces Th1-cell
  differentiation
• IL-18
• TNF-a
• Activates vascular endothelium and increases
  vascular permeability, leading to accumulation of
  Ig and complement in infected tissues

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Other Mediators and Molecules

• Phagocytes
• Toxic oxygen radicals
• Peroxides
• Nitric oxide (NO)
• Lipid mediators of inflammation
• Prostaglandins
• LTB4
• Platelet activating factor
• Complement component C5a
• Stimulates mast cells to release histamine,
  serotonin and LTB4
• IL-1, IL-6 and TNF-a
• Induce acute-phase response in liver
• Induce fever
• IL-1 and IL-18 signaling pathways activate NF-kB,
  important in innate immunity

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Immune Cells and Innate Immunity

• Phagocytes
• Neutrophils
• Moncyte/macrophage
• Eosinophils (to a lesser extent)
• NK cells (large granular lymphocytes)
• Antibody-dependent cell-mediated cytotoxicity
  (ADCC)
• Have two major functions
• Lysis of target cells
• Production of cytokines (IFN-g and TNF-a)
• Act against intracellular pathogens
• Herpesviruses
• Leishmania
• Listeria monocytogenes
• Act against protozoa
• Toxoplasma
• Trypanasoma

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Immune Cells and Innate Immunity (contd)

• g/d T cells
• Two types of T cell receptors
• One composed of a and b chains (basic T cell
  antigen receptor)
• One composed of g and d chains (minor population
  of T cells)
• Two groups of g/d T cells
• One group found in lymphoid tissues
• One group located in paracellular space between
  epithelial cells
• Recognizes unprocessed target antigen in absence
  of APC help
• B-1 cells (minor fraction of B cells, do not
  require T-cell help)
• Mast cells
• Located in serosa, under epithelial surfaces and
  adjacent to blood vessels, nerves and glands
• Capable of phagocytosis
• Process and present antigen using MHC class I or
  II receptors
• LPS can directly induce release of mast cell
  mediators
• Complement (C3a and C5a) induce mast cells to
  release mediators
• Chemotaxis, complement activation, inflammation
• TNF-a secreted by mast cells results in
  neutrophil influx into infected site

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Summary of Innate Immunity

• External and mechanical barriers
• Receptors for pathogen motifs
• Soluble antimicrobial proteins
• Pattern of cytokines produced influences adaptive
  response

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Adaptive Immunity and Infection
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Protective Role of Antibodies Against Pathogens

• Toxin neutralization
• Opsonization/enhancement of phagocytosis
• Sensitization for killing by NK cells
• Sensitization of mast cells
• Activation of complement system

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Toxin Neutralization
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Diseases caused by bacterial toxins
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Preventing Bacterial Adherence
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Virus-blocking Antibodies
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Activation of the Complement Cascade

• Cell Activation (anaphylatoxins)
• Activate inflammatory cells
• Induce smooth muscle contraction and blood vessel
  permeability
• Cytolysis ("membrane attack complexes)
• Loss of cell membrane integrity
• Opsonization
• Complement receptors on phagocytic cells
• Renders cells vulnerable to phagocytosis

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Fc Receptors
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Opsonization and Immune Adherence

• C3B (C4B)
• Facilitates adherence of bacteria, viruses and
  neutrophils to monocytes and macrophages
• Facilitates ingestion of certain bacteria by
  neutrophils and monocytes
• Facilitates ingestion by activated macrophages
• Augments mediated phagocytosis and IgG-mediated
  cell cytotoxicity (ADCC)
• Antibody
• antibody may opsonize by itself, or bridge
  phagocyte and target cell, enhancing complement
  immune adherence

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Chemotaxis
capillary blood vessel
phagocyte
endothelium
basement membrane
Site of inflammation, tissue damage and immune
reactions
PAVEMENTING
C5a
DIAPEDESIS
CHEMOTAXIS
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Phagocytosis
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Bactericidal Agents in Phagocytic Cells
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Natural Killer Cells and Antibody-Dependent
Cell-Mediated Cytotoxicity (ADCC)
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Inflammation
The four cardinal signs of inflammation
(Cornelius Celsus, 30 BC to AD 38) rubor et
tumor cum calore et dolore redness and swelling
with heat and pain

• Increased blood supply to the infected area
• Increased capillary permeability
• Migration of leukocytes into tissues (Chemotaxis)