Post on 22-Oct-2015
description
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