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

• Published in: Blood Vol. 112; no. 5; pp. 1750 - 1758
• Main Authors: Wynn, James L., Scumpia, Philip O., Winfield, Robert D., Delano, Matthew J., Kelly-Scumpia, Kindra, Barker, Tolga, Ungaro, Ricardo, Levy, Ofer, Moldawer, Lyle L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-09-2008; The Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Animals; Animals, Newborn; Bacteremia - drug therapy; Bacteremia - immunology; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; Female; Human bacterial diseases; Immunity, Innate - drug effects; Immunobiology; Infectious diseases; Interferon Type I - biosynthesis; Male; Medical sciences; Membrane Glycoproteins - agonists; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Peritonitis - drug therapy; Peritonitis - immunology; Sepsis - drug therapy; Sepsis - immunology; Signal Transduction; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - immunology; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 8 - agonists; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology; Toll like receptor 7; Immunopathology; Agonist; Rodentia; Natural immunity; Toll like receptor; Inflammation; Immune deficiency; Bacteremia; Immunomodulator; Infection; Sepsis syndrome; Vertebrata; Mammalia; Mouse; Newborn animal; Predisposition; Resiquimod; Bacteriosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-01-130500

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.