title: TRIF-dependent innate immune activation is critical for survival to neonatal gram-negative sepsis.
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.
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Alex G
authors.initials: AG
authors.lastname: Cuenca
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Dallas N
authors.initials: DN
authors.lastname: Joiner
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Lori F
authors.initials: LF
authors.lastname: Gentile
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Angela L
authors.initials: AL
authors.lastname: Cuenca
authors.affiliation: Division of Neonatology, Department of Pediatrics Vanderbilt University, Nashville, TN 37232;
authors.forename: James L
authors.initials: JL
authors.lastname: Wynn
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Kindra M
authors.initials: KM
authors.lastname: Kelly-Scumpia
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Philip O
authors.initials: PO
authors.lastname: Scumpia
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Behrns
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Philip A
authors.initials: PA
authors.lastname: Efron
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Dina
authors.initials: D
authors.lastname: Nacionales
authors.affiliation: Department of Pathology, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Chao
authors.initials: C
authors.lastname: Lui
authors.affiliation: University of Florida College of Medicine and Dentistry, Gainesville, FL 32610; and.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Wallet
authors.affiliation: Department of Medicine, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610.
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
authors.affiliation: Department of Pathology, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610;
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Department of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, FL 32610; moldawer@surgery.ufl.edu.
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D016905:Gram-Negative Bacterial Infections / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D007370:Interferon Type I; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse