title: Protective immunity and defects in the neonatal and elderly immune response to sepsis.
abstract: Populations encompassing extremes of age, including neonates and elderly, have greater mortality from sepsis. We propose that the increased mortality observed in the neonatal and elderly populations after sepsis is due to fundamental differences in host-protective immunity and is manifested at the level of the leukocyte transcriptome. Neonatal (5-7 d), young adult (6-12 wk), or elderly (20-24 mo) mice underwent a cecal slurry model of intra-abdominal sepsis. Both neonatal and elderly mice exhibited significantly greater mortality to sepsis (p < 0.05). Neonates in particular exhibited significant attenuation of their inflammatory response (p < 0.05), as well as reductions in cell recruitment and reactive oxygen species production (both p < 0.05), all of which could be confirmed at the level of the leukocyte transcriptome. In contrast, elderly mice were also more susceptible to abdominal peritonitis, but this was associated with no significant differences in the magnitude of the inflammatory response, reduced bacterial killing (p < 0.05), reduced early myeloid cell activation (p < 0.05), and a persistent inflammatory response that failed to resolve. Interestingly, elderly mice expressed a persistent inflammatory and immunosuppressive response at the level of the leukocyte transcriptome, with failure to return to baseline by 3 d. This study reveals that neonatal and elderly mice have profoundly different responses to sepsis that are manifested at the level of their circulating leukocyte transcriptome, although the net result of increased mortality is similar. Considering these differences are fundamental aspects of the genomic response to sepsis, interventional therapies will require individualization based on the age of the population.
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
authors.forename: Lori F
authors.initials: LF
authors.lastname: Gentile
authors.forename: Dina C
authors.initials: DC
authors.lastname: Nacionales
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Lopez
authors.forename: Erin
authors.initials: E
authors.lastname: Vanzant
authors.forename: Angela
authors.initials: A
authors.lastname: Cuenca
authors.forename: Alex G
authors.initials: AG
authors.lastname: Cuenca
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ungaro
authors.forename: Ben E
authors.initials: BE
authors.lastname: Szpila
authors.forename: Shawn
authors.initials: S
authors.lastname: Larson
authors.forename: Anna
authors.initials: A
authors.lastname: Joseph
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Moore
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Philip A
authors.initials: PA
authors.lastname: Efron
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002432:Cecum / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000235:genetics* / Q000276:immunology; D007231:Infant, Newborn; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010537:Peritoneum / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D016019:Survival Analysis; D059467:Transcriptome / Q000235:genetics* / Q000276:immunology
chemical_list: D016207:Cytokines