The specific aims of this research proposal are to investigate the nature of the age-related susceptibility of the newborn and developing human infant to infection with clinically relevant bacterial pathogens. This will be accomplished by the examination of several parameters of phagocytic cell system in the normal infant. This project is based upon the hypothesis that due to maturational deficiencies in the phagocytic cell system, i.e., phagocytic cells, neutrophils (PMNs) and monocytes-macrophages (MONO), and nonspecific opsonins, i.e., fibronectin and complement components, the neonatal and young infant is at increased risk to certain severe bacterial infections. Parallel investigations will be conducted in ongoing experimental rat model systems in which maturational changes in the phagocytic cell response to challenge infection can be systematically and rigorously examined and compared with those of the human. Micro-assay procedures developed will be employed in longitudinal studies of a number of functional and biochemical cellular characteristics of both peripheral blood PMN obtained by heel stick from infants during their first week of life. In addition, the role of fibronectin in bacterial tissue adherence will be studied. Attempts will be made to correlate changes in the nonspecific phagocytic cell system with changes in susceptibility to bacteria associated with neonatal sepsis. We anticipate that through the combined approach of longitudinal studies of the human neonate and the animal model systems, it should be possible to delineate deficiencies in the immune system of the developing infant important in diagnosis and treatment. Moreover, these studies should not only provide suitable predictive markers for the identification of human infants at risk but may also form basis for developing new intervention strategies important in therapy of life threatening infections in the newborn.
