Blood Journal
Leading the way in experimental and clinical research in hematology

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

  1. James L. Wynn1,2,
  2. Philip O. Scumpia1,
  3. Robert D. Winfield1,
  4. Matthew J. Delano1,
  5. Kindra Kelly-Scumpia1,
  6. Tolga Barker3,
  7. Ricardo Ungaro1,
  8. Ofer Levy4, and
  9. Lyle L. Moldawer1
  1. From the Departments of 1Surgery,
  2. 2Pediatrics, and
  3. 3Medicine, University of Florida College of Medicine, Gainesville; and
  4. 4Department of Medicine, Division of Infectious Disease, Children's Hospital Boston and Harvard Medical School, Boston, MA

Abstract

Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell–directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b+ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

  • Submitted January 4, 2008.
  • Accepted June 20, 2008.
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