Submitted January 4, 2008
Accepted June 20, 2008
Defective innate immunity predisposes murine neonates to poor sepsis outcome, but is reversed by TLR agonists
James L Wynn, Philip O Scumpia, Robert D Winfield, Matthew J Delano, Kindra Kelly-Scumpia, Tolga Barker, Ricardo Ungaro, Ofer Levy, and Lyle L Moldawer*
Department of Pediatrics, University of Florida, Gainesville, Florida, United States
Department of Surgery, University of Florida, Gainesville, Florida, United States
Department of Medicine, University of Florida, Gainesville, Florida, United States
Department of Medicine, Division of Infectious Disease, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States
* Corresponding author; email: moldawer{at}surgery.ufl.edu.
Neonates exhibit an increased risk of sepsis mortality compared to 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 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.
