Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists.
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.
Wynn
James L
JL
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610-0286, USA.
Scumpia
Philip O
PO
Winfield
Robert D
RD
Delano
Matthew J
MJ
Kelly-Scumpia
Kindra
K
Barker
Tolga
T
Ungaro
Ricardo
R
Levy
Ofer
O
Moldawer
Lyle L
LL
D000818:Animals; D000831:Animals, Newborn; D016470:Bacteremia / Q000188:drug therapy / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007370:Interferon Type I / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
D007370:Interferon Type I; D008562:Membrane Glycoproteins; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors