Lecture 19Lecture 19Host Defense Against InfectionHost Defense Against Infection

Innate immunityInnate immunity

Adaptive ImmunityAdaptive Immunity

Response to Initial Infection Response to Initial Infection

Stages of Response to InfectionStages of Response to Infection

Course Course of Typical of Typical

Acute Acute InfectionInfection

Innate Host Defense MechanismsInnate Host Defense Mechanisms

Anatomic FactorsAnatomic Factors Mechanical FactorsMechanical Factors Biochemical FactorsBiochemical Factors

SkinSkin

Stratified and cornified epithelium provides a Stratified and cornified epithelium provides a mechanical barriermechanical barrier

Indigenous microbiota competes with pathogensIndigenous microbiota competes with pathogens Acid pH inhibits growth of disease producing Acid pH inhibits growth of disease producing

bacteriabacteria Bactericidal long chain fatty acids in sebaceous Bactericidal long chain fatty acids in sebaceous

gland secretionsgland secretions

Respiratory TractRespiratory Tract Upper Respiratory TractUpper Respiratory Tract

Nasal hairs induce turbulenceNasal hairs induce turbulence Mucous secretions trap particlesMucous secretions trap particles Mucous stream to the base of tongue where material is swallowedMucous stream to the base of tongue where material is swallowed Nasal secretions contain antimicrobial substancesNasal secretions contain antimicrobial substances Upper respiratory tract contains large resident floraUpper respiratory tract contains large resident flora

Lower Respiratory TractLower Respiratory Tract Particles trapped on mucous membranes of bronchi and bronchiolesParticles trapped on mucous membranes of bronchi and bronchioles Beating action of cilia causes mucociliary stream to flow up into the pharynx Beating action of cilia causes mucociliary stream to flow up into the pharynx

where it is swallowedwhere it is swallowed 90% of particles removed this way. Only smallest particles (<10µ in 90% of particles removed this way. Only smallest particles (<10µ in

diameter) reach alveolidiameter) reach alveoli

AlveoliAlveoli Alveolar macrophage rapidly phagocytize small particlesAlveolar macrophage rapidly phagocytize small particles

Alimentary TractAlimentary Tract General defense mechanismsGeneral defense mechanisms

Mucous secretionsMucous secretions Integrity of of mucosal epitheliumIntegrity of of mucosal epithelium Peristaltic motions of the gut propel contents downwardPeristaltic motions of the gut propel contents downward Secretory antibody and phagocytic cellsSecretory antibody and phagocytic cells

StomachStomach Generally sterile due to low pHGenerally sterile due to low pH

Small IntestineSmall Intestine Upper portion contains few bacteriaUpper portion contains few bacteria As distal end of ilieum is reached flora increasesAs distal end of ilieum is reached flora increases

ColonColon Enormous numbers of microorganismsEnormous numbers of microorganisms 50-60% of fecal dry weight is bacteria50-60% of fecal dry weight is bacteria

Genitourinary TractGenitourinary Tract MaleMale

No bacteria above urethrovesicular junctionNo bacteria above urethrovesicular junction Frequent flushing action of urineFrequent flushing action of urine Bactericidal substances from prostatic fluidBactericidal substances from prostatic fluid pH of urinepH of urine Bladder mucosal cells may be phagocyticBladder mucosal cells may be phagocytic Urinary sIgAUrinary sIgA

Female (Vagina)Female (Vagina) Large microbial population (lactobacilli)Large microbial population (lactobacilli) Microorganisms produce low pH due to breakdown of glycogen produced by Microorganisms produce low pH due to breakdown of glycogen produced by

mucosal cellsmucosal cells

EyeEye

Flushing action of tears which drain through the Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynxlacrimal duct and deposit bacteria in nasopharynx

Tears contain a high concentration of lysozyme Tears contain a high concentration of lysozyme (effective against gram positive microorganisms(effective against gram positive microorganisms

Innate Immune RecognitionInnate Immune Recognition All multicellular organisms are able to All multicellular organisms are able to

recognize and eliminate pathogensrecognize and eliminate pathogens Despite their extreme heterogeneity, Despite their extreme heterogeneity,

pathogens share highly conserved molecules, pathogens share highly conserved molecules, called “pathogen-associated molecular called “pathogen-associated molecular patterns” (patterns” (PAMPsPAMPs))

Host cells do not share PAMPs with pathogensHost cells do not share PAMPs with pathogens PAMPs are recognized by innate immune PAMPs are recognized by innate immune

recognition receptors called pattern-recognition receptors called pattern-recognition molecules/receptors (recognition molecules/receptors (PRMs/PRRsPRMs/PRRs))

Three Functional Classes of Three Functional Classes of PRRs/PRMsPRRs/PRMs

Endocytic receptorsEndocytic receptors Macrophage mannose receptorMacrophage mannose receptor Macrophage scavenger receptor (SR)Macrophage scavenger receptor (SR) Integrin CD11b:CD18Integrin CD11b:CD18

Secreted proteinsSecreted proteins Mannose-binding protein/lectinMannose-binding protein/lectin Pulmonary surfactant proteins A and Pulmonary surfactant proteins A and

DD C-reactive protein (CRP)C-reactive protein (CRP)

Signaling receptorsSignaling receptors Toll receptor familyToll receptor family

Endogenous Signals Induced by PAMPsEndogenous Signals Induced by PAMPs

Mediate inflammatory cytokinesMediate inflammatory cytokines Interleukin-1 (IL-1)Interleukin-1 (IL-1) IL-6IL-6 Tumor necrosis factor (TNF-Tumor necrosis factor (TNF- Type 1 interferon (INF-I)Type 1 interferon (INF-I) Major effector cytokinesMajor effector cytokines ChemokinesChemokines

Antigen-presenting cells recognize PAMPsAntigen-presenting cells recognize PAMPs Same APC processes pathogens into specific pathogen-derived Same APC processes pathogens into specific pathogen-derived

antigens and presents them with MHC encoded receptors to T-antigens and presents them with MHC encoded receptors to T-cellscells

T-cell responds only when presented with both signalsT-cell responds only when presented with both signals Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Different Effector Cytokines in Response to Different Pathogens (Th1 vs.

Th2)Th2)

Antimicrobial Antimicrobial Peptides/DefensinsPeptides/Defensins

Four hundred peptides described to dateFour hundred peptides described to date Defensins (3- 5-kD, four families in eukaryotes)Defensins (3- 5-kD, four families in eukaryotes)

-defensins (neutrophils and intestinal Paneth cells)-defensins (neutrophils and intestinal Paneth cells) -defensins (epithelial cells)-defensins (epithelial cells) Insect defensinsInsect defensins Plant defensinsPlant defensins

Defensins appear to act by binding to outer Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane of bacteria, resulting in increased membrane permeability.membrane permeability.

May also play a role in inflammation and wound May also play a role in inflammation and wound repairrepair

Complement SystemComplement System

Three pathways now knownThree pathways now known ClassicalClassical AlternativeAlternative Lectin or MBL pathway (binding to mannose-Lectin or MBL pathway (binding to mannose-

containing carbohydrates)containing carbohydrates) Host cells have complement regulatory Host cells have complement regulatory

proteins on their surface that protect them proteins on their surface that protect them from spontaneous activation of C3 moleculesfrom spontaneous activation of C3 molecules

Inflammatory Mediators in Innate Inflammatory Mediators in Innate ImmunityImmunity

Cytokines secreted by phagocytes in response to Cytokines secreted by phagocytes in response to infection include:infection include: IL-1 IL-1

activates vascular endothelium and lymphocytesactivates vascular endothelium and lymphocytes Increases adhesiveness of leukocytesIncreases adhesiveness of leukocytes

IL-6IL-6 Induces B-cell terminal maturation into Ig-producing plasma cellsInduces B-cell terminal maturation into Ig-producing plasma cells

IL-8IL-8 Induces expression of b2 integrin adhesion molecules on Induces expression of b2 integrin adhesion molecules on

neutrophils, leading to neutrophil migration to infection siteneutrophils, leading to neutrophil migration to infection site IL-12IL-12

Activates NK cells and induces Th1-cell differentiationActivates NK cells and induces Th1-cell differentiation IL-18IL-18 TNF-TNF-

Activates vascular endothelium and increases vascular permeability, Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissuesleading to accumulation of Ig and complement in infected tissues

Other Mediators and MoleculesOther Mediators and Molecules

PhagocytesPhagocytes Toxic oxygen radicalsToxic oxygen radicals PeroxidesPeroxides Nitric oxide (NO)Nitric oxide (NO) Lipid mediators of inflammationLipid mediators of inflammation

ProstaglandinsProstaglandins LTB4LTB4 Platelet activating factorPlatelet activating factor

Complement component C5aComplement component C5a Stimulates mast cells to release histamine, serotonin and LTB4Stimulates mast cells to release histamine, serotonin and LTB4

IL-1, IL-6 and TNF-IL-1, IL-6 and TNF- Induce acute-phase response in liverInduce acute-phase response in liver Induce feverInduce fever

IL-1 and IL-18 signaling pathways activate NF-IL-1 and IL-18 signaling pathways activate NF-B, important in B, important in innate immunityinnate immunity

Immune Cells and Innate ImmunityImmune Cells and Innate Immunity

PhagocytesPhagocytes NeutrophilsNeutrophils Moncyte/macrophageMoncyte/macrophage Eosinophils (to a lesser extent)Eosinophils (to a lesser extent)

NK cells NK cells (large granular lymphocytes)(large granular lymphocytes) Antibody-dependent cell-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicity

(ADCC)(ADCC) Have two major functionsHave two major functions

Lysis of target cellsLysis of target cells Production of cytokines (IFN-Production of cytokines (IFN- and TNF- and TNF-))

Act against intracellular pathogensAct against intracellular pathogens HerpesvirusesHerpesviruses LeishmaniaLeishmania Listeria monocytogenesListeria monocytogenes

Act against protozoaAct against protozoa ToxoplasmaToxoplasma TrypanasomaTrypanasoma

Immune Cells and Innate Immunity (cont’d)Immune Cells and Innate Immunity (cont’d)

// T cells T cells Two types of T cell receptorsTwo types of T cell receptors

One composed of One composed of and and chains (basic T cell antigen receptor) chains (basic T cell antigen receptor) One composed of One composed of and and chains (minor population of T cells) chains (minor population of T cells)

Two groups of Two groups of // T cells T cells One group found in lymphoid tissuesOne group found in lymphoid tissues One group located in paracellular space between epithelial cellsOne group located in paracellular space between epithelial cells

Recognizes unprocessed target antigen in absence of APC helpRecognizes unprocessed target antigen in absence of APC help B-1 cells (minor fraction of B cells, do not require T-cell help)B-1 cells (minor fraction of B cells, do not require T-cell help) Mast cellsMast cells

Located in serosa, under epithelial surfaces and adjacent to Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glandsblood vessels, nerves and glands

Capable of phagocytosisCapable of phagocytosis Process and present antigen using MHC class I or II receptorsProcess and present antigen using MHC class I or II receptors LPS can directly induce release of mast cell mediatorsLPS can directly induce release of mast cell mediators Complement (C3a and C5a) induce mast cells to release Complement (C3a and C5a) induce mast cells to release

mediatorsmediators Chemotaxis, complement activation, inflammationChemotaxis, complement activation, inflammation TNF-TNF- secreted by mast cells results in neutrophil influx into infected secreted by mast cells results in neutrophil influx into infected

sitesite

Summary of Innate ImmunitySummary of Innate Immunity

External and mechanical barriersExternal and mechanical barriers Receptors for pathogen motifsReceptors for pathogen motifs Soluble antimicrobial proteinsSoluble antimicrobial proteins Pattern of cytokines produced Pattern of cytokines produced

influences adaptive responseinfluences adaptive response

Adaptive Immunity and Adaptive Immunity and InfectionInfection

Protective Role of Antibodies Against PathogensProtective Role of Antibodies Against Pathogens

Toxin neutralizationToxin neutralization Opsonization/enhancement of phagocytosisOpsonization/enhancement of phagocytosis Sensitization for killing by NK cellsSensitization for killing by NK cells Sensitization of mast cellsSensitization of mast cells Activation of complement systemActivation of complement system

Toxin NeutralizationToxin Neutralization

Diseases Diseases caused by caused by

bacterial toxinsbacterial toxins

Preventing Bacterial Preventing Bacterial AdherenceAdherence

Virus-blocking AntibodiesVirus-blocking Antibodies

Activation of the Complement CascadeActivation of the Complement Cascade

Cell Activation (anaphylatoxins)Cell Activation (anaphylatoxins) Activate inflammatory cellsActivate inflammatory cells Induce smooth muscle contraction and blood vessel Induce smooth muscle contraction and blood vessel

permeabilitypermeability Cytolysis ("membrane attack complexes“)Cytolysis ("membrane attack complexes“)

Loss of cell membrane integrityLoss of cell membrane integrity OpsonizationOpsonization

Complement receptors on phagocytic cellsComplement receptors on phagocytic cells Renders cells vulnerable to phagocytosisRenders cells vulnerable to phagocytosis

Fc Fc ReceptorsReceptors

Opsonization and Immune AdherenceOpsonization and Immune Adherence

C3B (C4B)C3B (C4B) Facilitates adherence of bacteria, viruses and neutrophils to Facilitates adherence of bacteria, viruses and neutrophils to

monocytes and macrophagesmonocytes and macrophages Facilitates ingestion of certain bacteria by neutrophils and monocytesFacilitates ingestion of certain bacteria by neutrophils and monocytes Facilitates ingestion by activated macrophagesFacilitates ingestion by activated macrophages Augments mediated phagocytosis and IgG-mediated cell cytotoxicity Augments mediated phagocytosis and IgG-mediated cell cytotoxicity

(ADCC)(ADCC) AntibodyAntibody

antibody may opsonize by itself, or bridge phagocyte and target cell, antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherenceenhancing complement immune adherence

ChemotaxisChemotaxiscapillary blood vesselcapillary blood vessel

phagocytephagocyte

endothelium endothelium

basement basement membrane membrane

PAVEMENTING PAVEMENTING

DIAPEDESIS DIAPEDESIS

CHEMOTAXIS CHEMOTAXIS

C5a

Site of Site of inflammation, inflammation, tissue damage tissue damage and immune and immune reactionsreactions

PhagocytosisPhagocytosis

Bactericidal Agents in Phagocytic CellsBactericidal Agents in Phagocytic Cells

Natural Killer Cells and Antibody-Dependent Natural Killer Cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)Cell-Mediated Cytotoxicity (ADCC)

InflammationInflammation

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

The four cardinal signs of inflammation The four cardinal signs of inflammation (Cornelius Celsus, 30 BC to AD 38):(Cornelius Celsus, 30 BC to AD 38):

rubor et tumor cum calore et dolorerubor et tumor cum calore et dolore

redness and swelling with heat and painredness and swelling with heat and pain