title: A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4.
abstract: During bacterial infections, Toll-like receptor 4 (TLR4) signals through the MyD88- and TRIF-dependent pathways to promote pro-inflammatory and interferon (IFN) responses, respectively. Bacteria can inhibit the MyD88 pathway, but if the TRIF pathway is also targeted is unclear. We demonstrate that, in addition to MyD88, Yersinia pseudotuberculosis inhibits TRIF signaling through the type III secretion system effector YopJ. Suppression of TRIF signaling occurs during dendritic cell (DC) and macrophage infection and prevents expression of type I IFN and pro-inflammatory cytokines. YopJ-mediated inhibition of TRIF prevents DCs from inducing natural killer (NK) cell production of antibacterial IFNγ. During infection of DCs, YopJ potently inhibits MAPK pathways but does not prevent activation of IKK- or TBK1-dependent pathways. This singular YopJ activity efficiently inhibits TLR4 transcription-inducing activities, thus illustrating a simple means by which pathogens impede innate immunity.
authors.affiliation: Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Charles V
authors.initials: CV
authors.lastname: Rosadini
authors.affiliation: Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy; Unit of Cell Signalling and Innate Immunity, Humanitas Clinical and Research Center, Rozzano 20089, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Zanoni
authors.affiliation: Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Odendall
authors.affiliation: Graduate Program in Molecular Microbiology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Green
authors.affiliation: Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Paczosa
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Naomi H
authors.initials: NH
authors.lastname: Philip
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
authors.affiliation: Graduate Program in Molecular Microbiology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA; Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Mecsas
authors.affiliation: Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Kagan
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015011:Yersinia pseudotuberculosis / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001426:Bacterial Proteins; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C109227:YopP protein, Yersinia