Microglial Polarization: Brain Injury or Protection in Response to Intrauterine Infection

PROJECT SUMMARY Neurodevelopmental impairment remains the most vexing issue facing the clinical management of premature infants. Intrauterine infection and inflammation are significant causes of preterm birth potentially resulting in lifelong neurodevelopmental impairment, such as cerebral palsy, sensory and cognitive deficits and behavioral

difficulties. Ureaplasma parvum is a bacterial species that is a common cause of preterm labor induced by intrauterine infection. Antibiotic treatment (Azithromycin) of intrauterine infection by Ureaplasma has been shown to delay preterm labor and improve fetal lung and fetal hemodynamic outcomes in non-human primates (NHP),

which are the most clinically relevant animal model in which to study human preterm labor and fetal brain injury. However, mechanisms of neuroinflammation and perinatal brain injury, and the action of antibiotics on the fetal brain in relation to intrauterine infection remain poorly understood. Microglial polarization into pro- or anti-

inflammatory phenotypes is a mechanism by which systemic inflammation may cause neuroinflammation in the developing brain. In the current proposal, we aim to investigate whether intrauterine infection by Ureaplasma parvum results in perinatal brain microglial polarization, oligodendrocyte maturation arrest and white matter

injury. We will utilize our access to brain samples from a unique Fetal and Postnatal Non-Human Primate (NHP) Tissue Repository collected from preterm birth studies previously conducted in our cohort of pregnant rhesus macaques at ONPRC. Our NHP model of intrauterine UP infection represents a valuable opportunity and

clinically relevant model system in which to investigate the mechanisms of perinatal neuroinflammation associated with infection-induced preterm labor across fetal and early postnatal development. In Aim 1 we will assess microglial polarization in response to intrauterine infection and inflammation and maternal antibiotic

treatment in the fetal and postnatal preterm brain. Aim 2 will investigate mechanisms of oligodendrocyte progenitor cell maturation and myelination associated with intrauterine Ureaplasma infection. This proposal utilizes our team's extensive experience in studying pregnancy physiology and fetal neurodevelopment and uses

novel spatial transcriptomic techniques in our unique NHP model of prematurity. Successful completion of this study, utilizing available stored NHP fetal and postnatal brain samples, will provide essential data on the mechanisms of fetal neuroinflammation that will contribute to future preclinical studies of the treatment of preterm

labor and perinatal brain injury.