title: A neonatal model of intravenous Staphylococcus epidermidis infection in mice <24 h old enables characterization of early innate immune responses.
abstract: Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 10(6), 10(7), 10(8) colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-α. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities.
authors.affiliation: Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Kenny D
authors.initials: KD
authors.lastname: Kronforst
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Mancuso
authors.forename: Matthew
authors.initials: M
authors.lastname: Pettengill
authors.forename: Jana
authors.initials: J
authors.lastname: Ninkovic
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Power Coombs
authors.forename: Chad
authors.initials: C
authors.lastname: Stevens
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Donald
authors.initials: D
authors.lastname: Goldmann
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016470:Bacteremia / Q000097:blood / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D013212:Staphylococcus epidermidis / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015430:Weight Gain / Q000235:genetics / Q000276:immunology
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha