The human fetus and newborn are unusually susceptible to severe infection; prominant are infections due to intracellular pathogens, and pulmonary infections due to extracellular pathogens such as group B streptococci (GBS). Macrophage (M Phi) activation, which is mediated by a lymphokine(s), MPhi activation factor(s)(MAF), is an important mechanism for control of infection with intracellular pathogen(s). MPhi activation in vitro against the transplacentally acquired intracellular pathogen Toxoplasma gondii was found to be impaired in cells from newborns compared to those from adults. This appeared to be due to decreased production of MAF by newborn lymphocytes and decreased responsiveness by newborn MO to newborns' but not adults' MAF. This proposal seeks to define and characterize at a cellular and biochemical level the mechnism for these differences using Toxoplasma as a prototype pathogen and two types each of adult (monocyte-derived and peritoneal MPhi) and newborn (monocyte-derived and placental MPhi) MPhi. The nature of MAF and differences between adult and newborn response to MAF will be analyzed by assessing: 1. the identity of newborn and adult MAF with gamma interferon and its properties as determined by adsorption, molecular sieve, HPLC and chromatofocusing chromatography, 2. the role of interleukins 1 and 2 in decreased production of effective MAF by newborn cells, 3. possible decreased binding or uptake of gamma interferon and newborn MAF by newborn MPhi. To assess the hypothesis that deficiencies in newborn AM contribute to the increased risk of GBS pneumonia, newborn pigtailed monkeys will be used. This project will examine the hypotheses that deficiencies in newborn AM function are due in part to: 1. changes in newborn AM and AM membrane lipid composition from exposure to the high alveolar phospholipid concentration in newborn lungs, 2. the recent derivation of newborn AM from precursor blood or interstitial mononuclear phagocytes, 3. intrinsic differences between newborn and adult MPhi are hypothesized to play a lesser role. Newborn and adult AM function will be defined at a cellular and biochemical level using conventional and flow cytometric techniques. Results will be correlated with susceptibility to GBS lung infection. These studies, by increasing our understanding of the role of newborn MPhi in the newborns' susceptibility to infection, may allow future treatment of such infections to be directed at reversing deficiencies in host defenses, in addition to conventional antimicrobial therapy.
