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THE IMMUNE RESPONSE AGAINST INTRACELLULAR BACTERIA Examples of intracellular bacteria Intracellular replication of Listeria monocytogenes Immune responses to Listeria monocytogenes MHC I MHC II IL-12 NK cell CD4+ Th1 cell CD8+ cytotoxic T cell IFNγ Macrophage activation Escape of bacteria to the cytoplasm listeriolysin Lysis of macrophage Killing of bacteria in the macrophage Innate and adaptive immunity to intracellular bacteria Cellular and Molecular Immunology, 7th ed., 2014 Elservier Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes Cellular and Molecular Immunology, 7th ed., 2014 Elservier Mutual activation of macrophages and effector lymphocytes in the immune response to intracellular bacterial infections Infection by Mycobacterium tuberculosis Effector functions of macrophages Cellular and Molecular Immunology, 7th ed., 2014 Elservier Infected macrophages send signals that recruit nearby lymphocytes Uninfected macrophages and lymphocytes surround the infected cells They encase the infected cells in a “cage” of “extracellular matrix” proteins where they can stay for years! We are actually quite good at keeping TB at bay only one-third of exposed patients will become infected and only 3-5% develop TB in the first year Clin Microbiol Rev. 2003 July; 16(3): 463–496. Granulomatous disease can become quite extensive. Here are numerous confluent granulomas in a case of pulmonary tuberculosis Pulmonary granulomas. Granulomatous inflammation typically consists of epithelioid macrophages, giant cells, lymphocytes and fibroblasts. There may be some neutrophils. Role of T cells and cytokines in determining the outcome of infections Cellular and Molecular Immunology, 7th ed., 2014 Elservier Infection by mycobacterium leprae „Lepromatous” skin blebs Infectious bacteria Suppressed Th1 response No efficient protection Small lesion Minimal response Tuberculoid Vigorous T-cell response Local inflammation Balanced protection Granulomas Peripheral nerve damage SPECTRAL DISEASE DEPENDING ON THE IMMUNE RESPONSE Genetically/environmentally determined Th1/Th2 „Lepromatous” skin blebs Tuberculoid form The immune response to intracellular bacteria INNATE IMMUNITY Phagocytosis – neutrophil granulocyte macrophage NK cells – direct activation of macrophages by IFNγ macrophage – mediated activation by IL - 12 ACQUIRED IMMUNITY Cell mediated – macrophage activation by CD4+ Th1 cells activation of CD8+ cytotoxic T cells Granuloma - isolation of bacteria, which resist elimination localized inflammatory response Movie Allthree Evasion of immune mechanisms by intracellular bacteria Inhibition of phagolysosome formation Mycobacterium tuberculosis Legionella pneumophila Scavenging of reactive oxigen intermediates Mycobacterium leprae (phenolic glycolipid) Disruption of phagosome membrane, escape into cytoplasm Listeria monocytogenes (listeriolysin protein) THE IMMUNE RESPONSE TO PARASITES Unicellular protozoa Plasmodium (malaria) Toxoplasma The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to phagocytic killing and may even replicate within macrophages. Inoue SI et al. (2013) Front Immunol 4:258. The life cycle of Plasmodium Immune response Malaria TH1 cells – secretion of cytokines Role of antibody? Effector mechanism IFN-g, TNF activate macrophages, neutrophils to kill parasites Life cycle of Toxoplasma Immune response Toxoplasma Strong TH1 response Effector mechanism IFN-g, TNF activate macrophages, neutrophils to kill parasites Toxoplasma gondii, the „brain-hacker” parasite The genome of T. gondii encodes two aromatic hydroxylases that allow the parasite to synthesize dopamine. This may influence the behavior of seropositive indviduals (e.g. increased risk-taking). Recently, T. gondii infections have been correlated with many neuropsychiatric diseases: - schizophrenia (38 large cohort studies, strong positive correlation); - obsessive-compulsive disorder (7 large cohort studies, positive correlation) credit: DJP Feruson/University of Oxford Multicellular parasites (helminths) Trichina worm - Trichinella spiralis Broad fish tapeworm - Diphyllobothrium latum They are too large to be ingested by phagocytes. Immune response Effector mechanism TH2 cells --> IL-4, IL-5 Eosinophils kill IgE-coated --> IgE, eosinophils parasites (form of ADCC) Functions of Th2 cells Cellular and Molecular Immunology, 8th ed., 2015 Elservier Responses to intestinal helminths The role of T cell-mediated responses in defense against helminths Eosinophils are better at killing helminths than are other leukocytes; the TH2 response and IgE provide a mechanism for bringing eosinophils to helminths and activating the cells. Activated eosinophils attack parasites Eosinophil granulocytes Mast cells Features that characterize a protective immune response to a helminth infection Escape mechanisms of parasites • Poor antigenicity • Variations in surface structure – gene conversion • Alternating expression (Trypanosoma) • Privileged sites isolated from the immune system (cyst) • Intracellular (Leishmania, Toxoplasma) • Inhibition of phagosome and lysosome fusion (Toxoplasma) • Antigen masking by bound self proteins • Complement (DAF) like structures