Transcript Lecture 7 Host Defense Against Infection

Lecture 19
Host Defense Against Infection
Innate immunity
Adaptive Immunity
Response to Initial Infection
Stages of Response to Infection
Course
of Typical
Acute
Infection
Innate Host Defense Mechanisms
 Anatomic
Factors
 Mechanical Factors
 Biochemical Factors
Skin
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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
Respiratory Tract
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Upper Respiratory Tract
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Lower Respiratory Tract
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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
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 (<10µ in
diameter) reach alveoli
Alveoli
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Alveolar macrophage rapidly phagocytize small particles
Alimentary Tract
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General defense mechanisms
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Stomach
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Generally sterile due to low pH
Small Intestine
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Mucous secretions
Integrity of of mucosal epithelium
Peristaltic motions of the gut propel contents downward
Secretory antibody and phagocytic cells
Upper portion contains few bacteria
As distal end of ilieum is reached flora increases
Colon
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Enormous numbers of microorganisms
50-60% of fecal dry weight is bacteria
Genitourinary Tract
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Male
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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)
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Large microbial population (lactobacilli)
Microorganisms produce low pH due to breakdown of glycogen
produced by mucosal cells
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
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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)
Three Functional Classes of PRRs/PRMs
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Endocytic receptors
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Secreted proteins
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Macrophage mannose receptor
Macrophage scavenger receptor (SR)
Integrin CD11b:CD18
Mannose-binding protein/lectin
Pulmonary surfactant proteins A and D
C-reactive protein (CRP)
Signaling receptors
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Toll receptor family
Endogenous Signals Induced by PAMPs
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Mediate inflammatory cytokines
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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
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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)
Antimicrobial Peptides/Defensins
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Four hundred peptides described to date
Defensins (3- 5-kD, four families in eukaryotes)
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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
Complement System
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Three pathways now known
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Classical
Alternative
Lectin or MBL pathway (binding to mannosecontaining carbohydrates)
Host cells have complement regulatory proteins
on their surface that protect them from
spontaneous activation of C3 molecules
Inflammatory Mediators in Innate Immunity
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Cytokines secreted by phagocytes in response to infection
include:
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IL-1
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IL-6
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Induces expression of b2 integrin adhesion molecules on neutrophils, leading
to neutrophil migration to infection site
IL-12
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Induces B-cell terminal maturation into Ig-producing plasma cells
IL-8
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activates vascular endothelium and lymphocytes
Increases adhesiveness of leukocytes
Activates NK cells and induces Th1-cell differentiation
IL-18
TNF-a
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Activates vascular endothelium and increases vascular permeability, leading to
accumulation of Ig and complement in infected tissues
Other Mediators and Molecules
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Phagocytes
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Toxic oxygen radicals
Peroxides
Nitric oxide (NO)
Lipid mediators of inflammation
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Complement component C5a
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Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-a
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Prostaglandins
LTB4
Platelet activating factor
Induce acute-phase response in liver
Induce fever
IL-1 and IL-18 signaling pathways activate NF-kB, important in
innate immunity
Immune Cells and Innate Immunity
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Phagocytes
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Neutrophils
Moncyte/macrophage
Eosinophils (to a lesser extent)
NK cells
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Antibody-dependent cell-mediated cytotoxicity (ADCC)
Have two major functions
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Lysis of target cells
Production of cytokines (IFN-g and TNF-a)
Act against intracellular pathogens
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(large granular lymphocytes)
Herpesviruses
Leishmania
Listeria monocytogenes
Act against protozoa
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Toxoplasma
Trypanasoma
Immune Cells and Innate Immunity (cont’d)
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g/d T cells
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Two types of T cell receptors
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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
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One group found in lymphoid tissues
One group located in paracellular space between epithelial cells
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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
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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
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Chemotaxis, complement activation, inflammation
TNF-a secreted by mast cells results in neutrophil influx into infected site
Summary of Innate Immunity
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External and mechanical barriers
Receptors for pathogen motifs
Soluble antimicrobial proteins
Pattern of cytokines produced influences
adaptive response
Adaptive Immunity and Infection
Protective Role of Antibodies Against Pathogens
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Toxin neutralization
Opsonization/enhancement of phagocytosis
Sensitization for killing by NK cells
Sensitization of mast cells
Activation of complement system
Toxin Neutralization
Diseases
caused by
bacterial toxins
Preventing Bacterial
Adherence
Virus-blocking Antibodies
Activation of the Complement Cascade
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Cell Activation (anaphylatoxins)
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Cytolysis ("membrane attack complexes“)
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Activate inflammatory cells
Induce smooth muscle contraction and blood vessel
permeability
Loss of cell membrane integrity
Opsonization
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Complement receptors on phagocytic cells
Renders cells vulnerable to phagocytosis
Fc
Receptors
Opsonization and Immune Adherence
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C3B (C4B)
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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
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antibody may opsonize by itself, or bridge phagocyte and target
cell, enhancing complement immune adherence
Chemotaxis
capillary blood vessel
phagocyte
endothelium
basement
membrane
PAVEMENTING
C5a
DIAPEDESIS
Site of
inflammation,
tissue damage
and immune
reactions
CHEMOTAXIS
Phagocytosis
Bactericidal Agents in Phagocytic Cells
Natural Killer Cells and Antibody-Dependent
Cell-Mediated Cytotoxicity (ADCC)
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)