Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Investigations of the neonatal-host immune response to sepsis and its impact on poor long-term outcomes have lagged behind older children and adults. During my fellowship training I developed and validated a clinically-relevant neonatal murine model of polymicrobial sepsis to analyze the neonatal-specific immune response to sepsis-causing agents. We found that neonates exhibit an attenuated innate immune response and are more susceptible to sepsis compared to young adults. Specifically, septic murine neonates produced up to 60 times less IL-1 than adults. IL-1 production, critical for innate immune cellular function, is intimately linked to inflammasome function. Therefore, we propose to explore the role of inflammasome signaling during murine neonatal sepsis using transgenic knockout mice lacking key inflammasome components. Next, we will determine the differences between neonates and adults in upstream and downstream inflammasome signaling (inflammasome-specific mRNA expression and protein production) following activation of innate immunity receptors (TLRs). Lastly, we will determine the role of enhanced inflammasome activation (using a genetic knock-in humanized mouse) or administration of its mature (active) products (IL-1, IL-18) as potential therapies for neonatal sepsis. Cumulatively, we will search for hitherto unknown features of inflammasome development during ontogeny and generate new knowledge about currently poorly understood parameters of the neonatal sepsis through determination of the role of inflammasome signaling. Thus, determining the impact of specific deficiencies in inflammasome components on neonatal vs. adult sepsis and providing direct proof about their potential importance in the susceptibility to and outcome of neonatal sepsis will represent major advance in this research front. Moreover, this investigation will help in the development of much needed biomarkers for neonatal sepsis susceptibility and identification of novel targets for therapy, such as inflammasome gain-offunction immunotherapy directed at improving sepsis outcomes. We will identify the differences in inflammasome signaling intermediates that result in the large discrepancy in IL-1 production between septic neonates and adults. Identification of mechanism(s) behind this large difference will allow development of targeted approaches that may lead to improved outcomes. We will thus explore the potential for translational value of inflammasome activation or for provision of its mature products as novel immunotherapies for neonatal sepsis in the aftermath of the negative outcome of intravenous immunoglobulin therapy for neonatal sepsis in a recent multicenter trial (NEJM 2011). We surmise that our focus on one of the most challenging problems in neonatology is consistent with the NIGMS' strategic mission to develop the foundation for advances in disease diagnosis, treatment and prevention as well as development of the next generation of physician-scientists.
Newborns, particularly those born prematurely, have a very high risk of death or life-long complications due to systemic infections-associated sepsis known also as 'blood poisoning'-despite being treated with antimicrobial drugs. We discovered that a key blood protein interleukin 1?, which is important for defense against infections, is grossly deficient in neonatal sepsis. In this proposal, we will determine the mechanism for this defect and new means to improve diagnosis and treatment of neonatal sepsis.
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