TRIF-dependent innate immune activation is critical for survival to neonatal gram-negative sepsis

J Immunol. 2015 Feb 1;194(3):1169-77. doi: 10.4049/jimmunol.1302676. Epub 2014 Dec 29.

Abstract

Current evidence suggests that neonatal immunity is functionally distinct from adults. Although TLR signaling through the adaptor protein, MyD88, has been shown to be critical for survival to sepsis in adults, little is known about the role of MyD88 or TRIF in neonatal sepsis. We demonstrate that TRIF(-/-) but not MyD88(-/-) neonates are highly susceptible to Escherichia coli peritonitis and bacteremia. This was associated with decreased innate immune recruitment and function. Importantly, we found that the reverse was true in adults that MyD88(-/-) but not TRIF(-/-) or wild-type adults are susceptible to E. coli peritonitis and bacteremia. In addition, we demonstrate that TRIF but not MyD88 signaling is critical for the TLR4 protective adjuvant effect we have previously demonstrated. These data suggest a differential requirement for the survival of neonates versus adults to Gram-negative infection, and that modulation of TRIF in neonates can be used to augment survival to neonatal sepsis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics*
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Animals, Newborn
  • Chemokine CXCL10 / metabolism
  • Chemokines / biosynthesis
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Disease Susceptibility / immunology
  • Escherichia coli / immunology
  • Female
  • Genetic Predisposition to Disease
  • Gram-Negative Bacterial Infections / genetics*
  • Gram-Negative Bacterial Infections / immunology*
  • Gram-Negative Bacterial Infections / metabolism
  • Gram-Negative Bacterial Infections / microbiology
  • Gram-Negative Bacterial Infections / mortality
  • Granulocytes / immunology
  • Granulocytes / metabolism
  • Immunity, Innate*
  • Interferon Type I / metabolism
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phagocytosis / genetics
  • Phagocytosis / immunology
  • Reactive Oxygen Species / metabolism
  • Sepsis / genetics*
  • Sepsis / immunology*
  • Sepsis / metabolism
  • Sepsis / microbiology
  • Sepsis / mortality
  • Toll-Like Receptors / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • Chemokine CXCL10
  • Chemokines
  • Cytokines
  • Interferon Type I
  • Reactive Oxygen Species
  • TICAM-1 protein, mouse
  • Toll-Like Receptors