title: Multiple MyD88-dependent responses contribute to pulmonary clearance of Legionella pneumophila.
abstract: MyD88-dependent signalling is important for secretion of early inflammatory cytokines and host protection in response to Legionella pneumophila infection. Although toll-like receptor (TLR)2 contributes to MyD88-dependent clearance of L. pneumophila, TLR-independent functions of MyD88 could also be important. To determine why MyD88 is critical for host protection to L. pneumophila, the contribution of multiple TLRs and IL-18 receptor (IL-18R)-dependent interferon-gamma (IFN-gamma) production in a mouse was examined. Mice deficient for TLR5 or TLR9, or deficient for TLR2 along with either TLR5 or TLR9, were competent for controlling bacterial replication and had no apparent defects in cytokine production compared with control mice. MyD88-dependent production of IFN-gamma in the lung was mediated primarily by natural killer cells and required IL-18R signalling. Reducing IFN-gamma levels did not greatly affect the kinetics of L. pneumophila replication or clearance in infected mice. Additionally, IFN-gamma-deficient mice did not have a susceptibility phenotype as severe as the MyD88-deficient mice and were able to control a pulmonary infection by L. pneumophila. Thus, MyD88-dependent innate immune responses induced by L. pneumophila involve both TLR-dependent responses and IL-18R-dependent production of IFN-gamma by natural killer cells, and these MyD88-dependent pathways can function independently to provide host protection against an intracellular pathogen.
authors.affiliation: Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. craig.roy@yale.edu
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Archer
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
mesh_terms: D000818:Animals; D015169:Colony Count, Microbial; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency; D007694:Killer Cells, Natural / Q000276:immunology; D016952:Legionella pneumophila / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D053724:Receptors, Interleukin-18 / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000172:deficiency / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053724:Receptors, Interleukin-18; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma
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