IMMUNITY TO MICROBES

IMMUNOLOGY

Disease pathogenesis depends on:

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent •Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

Streptococcus - extracellular

Q fever bacteria - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

Streptococcus - extracellular

Q fever bacteria - intracellular

Influenza - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

Streptococcus - extracellular

Candida - extracellular

Q fever bacteria - intracellular

Influenza - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

Streptococcus - extracellular

Candida - extracellular

Q fever bacteria - intracellular

Influenza - intracellular

Plasmodium - intracellular

IMMUNOLOGY

Disease pathogenesis depends on:

•Type of infectious agent•Target organ•Localization of the pathogen•Type of immune response

•Bacteria•Viruses•Fungi•Parasites

Q fever bacteria - intracellular

Streptococcus - extracellular

Q fever bacteria - intracellular

Influenza - intracellular

Plasmodium - intracellular

IMMUNOLOGY

Immune response• The two-dimensional response chart

Self

Non-self

Safe Dangerous

IMMUNOLOGY

Immune response• The two-dimensional response chart

Self

Non-self

Safe Dangerous

[cancer cell]

[infectious agents]

[autologus molec.]

[food]

IMMUNOLOGY

Immune response• The two-dimensional response chart

Self

Non-self

Safe Dangerous

Tolerate Damage

EliminateIgnore

[cancer cell]

[infectious agents]

[autologus molec.]

[food]

IMMUNOLOGY

Understanding the immunology of ID

• host-parasite interactions differ among individuals

• the outcome depends on characteristics of the host as well as of the microbe

• both hosts and parasites are engaged in a fitness-enhancing adaptive race

• trade-off between over- and under- reactivity – too much and too little is equally bad

IMMUNOLOGY

Understanding the immunology of ID

• host-parasite interactions differ among individuals

• the outcome depends on characteristics of the host as well as of the microbe

• both hosts and parasites are engaged in a fitness-enhancing adaptive race

• trade-off between over- and under- reactivity – too much and too little is equally bad

Why would a disease-predisposing genotype be selected?

IMMUNOLOGY

Understanding the immunology of ID

• host-parasite interactions differ among individuals

• the outcome depends on characteristics of the host as well as of the microbe

• both hosts and parasites are engaged in a fitness-enhancing adaptive race

• trade-off between over- and under- reactivity – too much and too little is equally bad

Why would a disease-predisposing genotype be selected?

IMMUNOLOGY

The lens metaphor

Signal Decision Response

Infection HarmTLRs

INNATE

ADAPTIVE

Malfunctional(autoimmunity)

Malfunctional(allergy)

Functional

Skin

Mucosa

CNS

IMMUNOLOGY

Cell-mediated immune response

Intracellular Antigen

Activated T cells

Cytotoxic T cells Helper T cells

Infected Cells

MHC I

Attack by perforins

StimulationTh1 Inflammatory

Th2 Activate B cells

IMMUNOLOGY

Humoral immune response

Extracellular Antigen

Activated T cells

Plasma cells

Helper T cells

Extracellular pathogen

MHC II

Attack by antibodies

StimulationActivated B cells

T-independentactivation

Antibody Function

IgMActivates the complement system, leading to opsonization and phagocytosis

IgGBlocks virus entry into host cells. Promotes phagocytosis by macrophages

IgEResponds to many helminthic parasites by participating in eosinophil-mediated killing of the helminths

IgAPlays a key role in mucosal immunity

IgDFunction unknown. Only present in minute quantities in the serum.

IMMUNOLOGY

Immunity to extracellular bacteria• Streptococcus pneumoniae

•encapsulated gram-positive coccus•teichoic acid rich in phosphocholine (C-polysaccharide) and autolytic enzyme (amidase) in cell wall

•F antigen•pneumolysin

Pathogenesis• colonizes the oropharynx (surface protein adhesions)• spreads into normally sterile tissues (pneumolysin, IgA, protease)• stimulates local inflammatory response (teichoic acid, peptidoglycan fragments, pneumolysin)• evades phagocytic killing (polysaccharide capsule)

Tissue destruction•Complement activation (inflammatory C3a, C5a)•Secretion of cytokines (IL-1, TNF)•Secretion of H2O2

•PC binds receptors for PAF

Phagocytic survival•Capsule inhibits phagocytosis•Cytotoxic (pneumolysin)

Innate immunity•Complement activation (alternative & classical pathways)•TLR2 (PG , LTA); TLR4 (pneumolysin)•SIGN-R1 on macrophages•B-1a cells make IgM to polysaccharides w/o prior exposure

Specific immunity•Anticapsular antibody (5-8d after the onset of infection)•Antibodies to other constituents?•Low prevalence of anticapsular Ab•Spleen clears unopsonized bacteria from bloodstream (!splenectomy)

IMMUNOLOGY

Immunity to intracellular bacteria• Mycobacterium tuberculosis

•intracellular pathogen in unactivated alveolar macrophages

Innate immunity•Macrophages secrete IL-12 and TNF-α•Inflammation and recruitment of NK and T cells

Specific immunity•Th1-type response, with secretion of IFN-γ•Macrophages are activated in the presence of IFN-γ, leading to phagolysosome fusion and enhanced intracellular killing

Pathogenesis• M. tuberculosis enters the respiratory airways • infectious particles penetrate to the alveoli• is phagocytized by alveolar macrophages• intravacuole replication

Phagocytic survival•prevents fusion of the phagosome with the lysosomes by blocking EEA-1

Tissue destruction•Inflammation•Cell-mediated responses•Granulomas

IMMUNOLOGY

Immunity to viruses• West Nile virus

•Flavivirus, arbovirus•enveloped, single-stranded, positive-sense RNA•cytolytic, buds into intracellular vesicles•target: monocytes, macrophages, endothelial cells•good inducers of IFN (flu-like symptoms)

Humoral immunity•Double-stranded RNA intermediate (TLR3) is a good inducer of IFNα and β

•Circulating antibodies (IgM and IgG) - double -edged sword•Cross-reactivity of Ab to flaviviruses

Cellular immunity•CNS expression of CCR5 and CCL5 are upregulated by WN →recruitment of CD4+, CD8+ and NK cells

IMMUNOLOGY

Immunity to parasites

• Leishmania donovani•Protozoan•Visceral leishmaniasis, but also CL and ML•Promastigote to amastigote in macrophages

Immune evasion

Immune response•Mostly rely on adaptive immunity•Leishmania-specific Th1-type CD4+ T cells that secrete interferon-γ (INF-γ) and interleukin-2 (IL-2)•IFN-γ activates macrophages to kill amastigotes•IL-1 and TNF prime macrophages for activation by INF-γ•IL-12 early role•Progressive disease seems to be associated with a Th2-type response (activation of B cells and production of antibodies, IL-10 and TGF-β

IMMUNOLOGY

Immunity to fungi• Aspergillus fumigatus

•Invasive aspergillosis is a major cause of morbidity and mortality in immunosuppressed patients

•Uncommon in immunocompetent hosts

Innate immunity•Pulmonary macrophages ingest and kill conidia

•Neutrophils extracellularly kill conidia and hyphae

•Toxins may inhibit macrophages and neutrophils

•TLR2 and dectin-1recognition results in secretion of proinflammatory cytokines

Adaptive immunity•Antibodies are common but not protective•Th1 response is associated with a favorable outcome