title: Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4 and -9.
abstract: The role of Toll-like receptors (TLR) and MyD88 for immune responses to Mycobacterium tuberculosis (Mtb) infection remains controversial. To address the impact of TLR-mediated pathogen recognition and MyD88-dependent signaling events on anti-mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple- and MyD88-deficient mice. After aerosol infection, both TLR2/4/9-deficient and wild-type mice expressed pro-inflammatory cytokines promoting antigen-specific T cells and the production of IFN-gamma to similar extents. Moreover, TLR2/4/9-deficient mice expressed IFN-gamma-dependent inducible nitric oxide synthase and LRG-47 in infected lungs. MyD88-deficient mice expressed pro-inflammatory cytokines and were shown to expand IFN-gamma-producing antigen-specific T cells, albeit in a delayed fashion. Only mice that were deficient for MyD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9-deficient mice controlled Mtb replication. IFN-gamma-dependent restriction of mycobacterial growth was severely impaired only in Mtb-infected MyD88, but not in TLR2/4/9-deficient bone marrow-derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, -4, and -9, nor MyD88 are required for the induction of adaptive T cell responses. Rather, MyD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti-mycobacterial defense.
authors.affiliation: Junior Research Group Molecular Infection Biology, Research Center Borstel, Borstel, Germany. choelscher@fz-borstel.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.forename: Ulrich E
authors.initials: UE
authors.lastname: Schaible
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hölscher
authors.forename: Clara
authors.initials: C
authors.lastname: Bathmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Korbel
authors.forename: Insa
authors.initials: I
authors.lastname: Lenz
authors.forename: Tanja
authors.initials: T
authors.lastname: Sonntag
authors.forename: Svenja
authors.initials: S
authors.lastname: Kröger
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Horst
authors.initials: H
authors.lastname: Mossmann
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Marina
authors.initials: M
authors.lastname: Freudenberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
mesh_terms: D000825:Animal Structures / Q000382:microbiology; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; C096000:Ifi1 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019204:GTP-Binding Proteins