title: Innate immune responses to Rhodococcus equi.
abstract: We examined innate immune responses to the intracellular bacterium Rhodococcus equi and show that infection of macrophages with intact bacteria induced the rapid translocation of NF-kappa B and the production of a variety of proinflammatory mediators, including TNF, IL-12, and NO. Macrophages from mice deficient in MyD88 failed to translocate NF-kappa B and produced virtually no cytokines in response to R. equi infection, implicating a TLR pathway. TLR4 was not involved in this response, because C3H/HeJ macrophages were fully capable of responding to R. equi infection, and because RAW-264 cells transfected with a dominant negative form of TLR4 responded normally to infection by R. equi. A central role for TLR2 was identified. A TLR2 reporter cell was activated by R. equi, and RAW-264 cells transfected with a dominant negative TLR2 exhibited markedly reduced cytokine responses to R. equi. Moreover, macrophages from TLR2(-/-) mice exhibited diminished cytokine responses to R. equi. The role of the surface-localized R. equi lipoprotein VapA (virulence-associated protein A), in TLR2 activation was examined. Purified rVapA activated a TLR2-specific reporter cell, and it induced the maturation of dendritic cells and the production of cytokines from macrophages. Importantly, TLR2(-/-)-deficient but not TLR4(-/-)-deficient mice were found to be compromised in their ability to clear a challenge with virulent R. equi. We conclude that the efficient activation of innate immunity by R. equi may account for the relative lack of virulence of this organism in immunocompetent adults.
authors.affiliation: Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.forename: Maria Chiara G
authors.initials: MC
authors.lastname: Monaco
authors.forename: Shruti
authors.initials: S
authors.lastname: Jain
authors.forename: Mary K
authors.initials: MK
authors.lastname: Hondalus
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: David M
authors.initials: DM
authors.lastname: Mosser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D001426:Bacterial Proteins / Q000276:immunology / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007121:Immunocompetence; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016929:Rhodococcus equi / Q000276:immunology* / Q000472:pathogenicity; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014774:Virulence; D037521:Virulence Factors / Q000276:immunology / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D018664:Interleukin-12; D009569:Nitric Oxide