The central goal of this project is to understand the role of innate immunity in infections caused by Group B streptococci (S. agalactiae or GBS). GBS are the major cause of neonatal sepsis and meningitis and thus a leading cause of neonatal morbidity and mortality. GBS-induced inflammatory mediators include tumor necrosis factor (TNF) that, when excessive, can contribute to host morbidity and mortality. Recent evidence suggests that a variety of Gram-positive bacterial surface molecules activate the innate immune system via phagocyte innate immune receptors including cellular differentiation antigen-14 (CD14), complement receptors-3 and -4 (CR3/4), and Toll-like receptor 2 (TLR2). The candidate will further characterize bacterial and host determinants of innate immunity to GBS and test the following hypotheses: Specific molecular interactions between GBS surface components and phagocyte innate immune receptors mediate the host inflammatory response to GBS infection, that such responses are down-regulated by neutrophil-derived antimicrobial peptides that bind and neutralize inflammatory GBS surface molecules, and that these pro- and anti-inflammatory innate immune responses differ between newborns and adults.
In Aim 1, GBS surface components that activate host phagocytes (i.e., neutrophils and monocytes) will be identified and characterized.
In Aim 2, newborn and adult phagocytes will be compared with respect to expression and function of CR3/4, CD14, and TLR2.
In Aim 3, putative neutrophil-derived peptides with anti-inflammatory activity against GBS will be isolated and characterized. The candidate seeks an intensive, formal, mentored training as preparation for becoming an independent scientist. As a specialist in pediatric infectious diseases, his long-term goal is to identify molecular pathways of innate immunity that might someday be modulated to improve outcomes of GBS and other bacterial infections in neonates.
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