Novel Mechanisms and Approaches to Treat Neonatal Sepsis

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DESCRIPTION (provided by applicant): One million newborn children die each year from sepsis. Mortality rates among these children range from 10-40% depending on birth weight and age at onset of sepsis, but are especially high in very low birth weight infants (VLBW). Very little is known about how neonates differ from young adults, and thus, therapeutic opportunities are limited and often based on therapies meant for adults. Based on our published and preliminary observations, our central belief is that the neonate has greater risk to sepsis- induced organ injury and mortality because of differences in adaptor signaling in the early innate immune response. More specifically, we propose that TRIF signaling leading to downstream CXCL10 production is defective in neonates, and that neonate survival to sepsis is adversely affected by these defective signaling pathways. Our specific aims are to (1) characterize the importance of TRIF-dependent signaling in neonatal versus adult murine sepsis, (2) determine the role of TRIF-dependent CXCL10 production in murine neonatal sepsis, and, (3) identify the role of TRIF and CXCL10 signaling pathways as a 'target' for therapeutic modality for murine neonatal sepsis. We will use a neonatal mouse model of polymicrobial peritonitis (sepsis) that we have developed and validated, and evaluate the importance of TRIF signaling and CXCL10 through both genetic (TRIF-/-, MyD88-/- knockouts) and pharmacologic approaches. Post-partum day 4-7 mice (neonate) and 5-7 week old mice (young adult) will have sepsis induced. In some cases, TRIF and MyD88 signaling pathways will be eliminated by using knockout mice and the dependence of these pathways on CXCL10 production and antimicrobial responses will be evaluated. Similarly, we will block CXCL10 activity pharmacologically. The alternative approach will be to use TLR agonists and CXCL10 as an adjuvant for neonatal mice subjected to polymicrobial sepsis, and evaluate outcomes and antimicrobial responses. These studies will lead to a better fundamental understanding of the neonatal response to sepsis and elucidate possible pathways that may be used to augment neonatal responses. Importantly, this application addresses multiple "Healthy People 2010" objectives to reduce infant morbidity and mortality related to sepsis, and may lead to the discovery of novel therapeutics that will enhance the survival of these particularly susceptible children.