title: Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88.
abstract: Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88(-/-) macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88(-/-) mice with MTB is lethal within 4 weeks with 2 log(10) higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-gamma production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guerin conferred a substantial protection in MyD88(-/-) mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88(-/-) mice to control MTB infection.
authors.affiliation: CNRS, Molecular Immunology and Embryology, 3B rue de la Férollerie, 45071 Orléans, France.
authors.forename: Cecile M
authors.initials: CM
authors.lastname: Fremond
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yeremeev
authors.forename: Delphine M
authors.initials: DM
authors.lastname: Nicolle
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D002469:Cell Separation; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D009569:Nitric Oxide / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D019076:Transgenes; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D009569:Nitric Oxide; D007371:Interferon-gamma