Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity

John Sotolongo, Cecilia España, Andrea Echeverry, David Siefker, Norman Altman, Julia Zaias, Rebeca Santaolalla, Jose Ruiz, Kurt Schesser, Becky Adkins, Masayuki Fukata

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Toll-like receptor 4 (TLR4), which signals through the adapter molecules myeloid differentiation factor 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter inducing IFN-β (TRIF), is required for protection against Gram-negative bacteria. TRIF is known to be important in TLR3-mediated antiviral signaling, but the role of TRIF signaling against Gram-negative enteropathogens is currently unknown. We show that TRIF signaling is indispensable for establishing innate protective immunity against Gram-negative Yersinia enterocolitica. Infection of wild-type mice rapidly induced both IFN-β and IFN-γ in the mesenteric lymph nodes. In contrast, TRIF-deficient mice were defective in these IFN responses and showed impaired phagocytosis in regional macrophages, resulting in greater bacterial dissemination and mortality. TRIF signaling may be universally important for protection against Gram-negative pathogens, as TRIF-deficient macrophages were also impaired in killing both Salmonella and Escherichia coli in vitro. The mechanism of TRIFmediated protective immunity appears to be orchestrated by macrophage-induced IFN-β and NK cell production of IFN-γ. Sequential induction of IFN-β and IFN-γ leads to amplification of macrophage bactericidal activity sufficient to eliminate the invading pathogens at the intestinal interface. Our results demonstrate a previously unknown role of TRIF in host resistance to Gram-negative enteropathogens, which may lead to effective strategies for combating enteric infections.

Original languageEnglish (US)
Pages (from-to)2705-2716
Number of pages12
JournalJournal of Experimental Medicine
Volume208
Issue number13
DOIs
StatePublished - Dec 19 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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