Our sepsis-targeted observational human neonatal studies have been performed in parallel with our mechanistic murine studies. We used peripheral blood genome-wide expression profiling (GWEP) to demonstrate that among older age groups of children with septic shock, neonates exhibited a unique host response. In particular, neonates exhibited predominantly down-regulation of genes, comprising pathways of critical innate immune importance, whereas older pediatric patients showed predominantly up-regulated expression of these pathways. In a similar study of infants in the NICU, we showed that timing of sepsis after birth is a critical determinant of the host response to sepsis in preterm neonates. We are continuing our studies focused on the changes in peripheral blood and cell-specific GWEPs associated with sepsis in preterm infants. We are fortunate to have received funding from the NIH (NICHD R01HD089939) to use microfluidic measurements of preterm PMN function and transcriptomics to develop prediction models for sepsis, and ultimately, clinical outcome, using several novel, validated, microfluidic technologies that are robust and easy to use with little training. The low volume makes them particularly useful for preterm infants where sample volume is limited, and facilitates serial assessments with unprecedented temporal resolution of key functions of PMNs. These studies, integrated by bioinformatics approaches, will generate new tools for diagnosing sepsis in the newborn and predicting clinical outcomes.
We use large administrative EMR and research databases to uncover epidemiologic evidence of neonatal sepsis-related phenomena. In an analysis of nearly 140,000 preterm neonates from two large non-overlapping databases, we showed preterm neonates do not manifest clinically significant immunoparalysis after sepsis in contrast to adults and older children. We are currently investigating the progression of clinical and laboratory signs of multi-organ dysfunction in neonates with lethal sepsis as well as the impact of velocity of clinical and laboratory signs on survival. To help align the efforts of neonatal sepsis investigators worldwide to improve outcomes for our most vulnerable patients, we are actively developing an evidence-based consensus definition for neonatal sepsis that incorporates the preterm infant’s unique physiology. The University of Florida is home to the Sepsis and Critical Illness Research Center, the first of its kind in the nation, supported by a $12 million five-year grant from the National Institutes of Health.
In our initial studies, we developed and validated a murine neonatal model of generalized peritonitis to generate sepsis. 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 exhibits fundamental differences compared to the adult in the inflammatory response to sepsis; specifically a Th2-skewed plasma cytokine profile with 20-55 times less IL-1β, IFN-γ, and TNF-α. In subsequent publications using our model 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. In that report, we also demonstrated that innate immune priming 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. We showed the neonate has a strong dependence on TRIF-signaling, CXCR3, and CXCl10 for sepsis survival whereas the adult depends more heavily on MyD88 signaling. Recently, we showed murine neonatal CD71+ erythroid cells, although immunomodulatory ex vivo, had no impact on murine neonatal sepsis survival. Our newest work demonstrates the deleterious role of IL-18 in neonatal sepsis and is published in the Proceedings of the National Academy of Sciences and the subject of our NIGMS-funded R01 entitled Modifiable Determinants of Mortality in Neonatal Sepsis (R01HD089939). We are actively investigating other beneficial mechanisms of innate immune stimulation and detrimental mechanisms of sepsis.
We are very fortunate to have spectacular collaborators that make the work we do possible.
We are grateful to the agencies below that have provided support for our research program.