title: TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis.
abstract: To investigate the role of Toll-like receptor (TLR)9 in the immune response to mycobacteria as well as its cooperation with TLR2, a receptor known to be triggered by several major mycobacterial ligands, we analyzed the resistance of TLR9(-/-) as well as TLR2/9 double knockout mice to aerosol infection with Mycobacterium tuberculosis. Infected TLR9(-/-) but not TLR2(-/-) mice displayed defective mycobacteria-induced interleukin (IL)-12p40 and interferon (IFN)-gamma responses in vivo, but in common with TLR2(-/-) animals, the TLR9(-/-) mice exhibited only minor reductions in acute resistance to low dose pathogen challenge. When compared with either of the single TLR-deficient animals, TLR2/9(-/-) mice displayed markedly enhanced susceptibility to infection in association with combined defects in proinflammatory cytokine production in vitro, IFN-gamma recall responses ex vivo, and altered pulmonary pathology. Cooperation between TLR9 and TLR2 was also evident at the level of the in vitro response to live M. tuberculosis, where dendritic cells and macrophages from TLR2/9(-/-) mice exhibited a greater defect in IL-12 response than the equivalent cell populations from single TLR9-deficient animals. These findings reveal a previously unappreciated role for TLR9 in the host response to M. tuberculosis and illustrate TLR collaboration in host resistance to a major human pathogen.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA. abafica@niaid.nih.gov
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Charles A
authors.initials: CA
authors.lastname: Scanga
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Cynthia
authors.initials: C
authors.lastname: Leifer
authors.forename: Allen
authors.initials: A
authors.lastname: Cheever
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D016207:Cytokines; D017931:DNA Primers; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9