We developed and validated the gold standard of murine neonatal sepsis modeling: the cecal slurry model of generalized peritonitis (2007). This model permits in-depth mechanistic investigation of the neonatal-specific host immune response to sepsis through the application of pharmacologic and genetic (knock-in, knock-out, and humanized) approaches.
We showed the neonate, in stark contrast to the adult, does not depend on adaptive immunity or type I interferon signaling for a successful host response (2008). In that report, we also demonstrated that innate immune priming (trained immunity) using selected toll-like receptor agonists dramatically reduced subsequent sepsis mortality by up to 40 percent and was associated with enhanced innate immune cellular function.
Recently, we showed murine neonatal CD71+ erythroid cells, although immunomodulatory ex vivo, had no impact on murine neonatal sepsis survival (2015). We showed the deleterious role of IL-18 in neonatal sepsis and is published in the Proceedings of the National Academy of Sciences (2016) and the subject of our NIGMS-funded R01 entitled Modifiable Determinants of Mortality in Neonatal Sepsis (R01HD089939). We showed IL-1α and not IL-1β drives IL-1R1-dependent neonatal murine sepsis lethality, highlighting a potential mechanism behind the inability of anakinra to reduce sepsis mortality (2018)
We are actively investigating other beneficial mechanisms of innate immune stimulation and detrimental mechanisms of sepsis.
- Wynn JL, Scumpia PO, Delano MJ, et al. Increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis. Shock. 2007;28(6):675–683. doi:10.1097/SHK.0b013e3180556d09
- Wynn JL, Scumpia PO, Winfield RD, et al. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood. 2008;112(5):1750–1758. doi:10.1182/blood-2008-01-130500
- Wynn JL, Wilson CS, Hawiger J, et al. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proc Natl Acad Sci U S A. 2016;113(19):E2627–E2635. doi:10.1073/pnas.1515793113
- Benjamin JT, Moore DJ, Bennett C, et al. Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality. J Immunol. 2018;201(10):2873–2878. doi:10.4049/jimmunol.1801089