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Cell Host Microbe. 2015 Dec 9;18(6):682-93. doi: 10.1016/j.chom.2015.11.006.

A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4.

Author information

1
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
2
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.
3
Graduate Program in Molecular Microbiology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
4
Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
5
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
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.
7
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

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.

PMID:
26651944
PMCID:
PMC4685476
DOI:
10.1016/j.chom.2015.11.006
[Indexed for MEDLINE]
Free PMC Article

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