Intrauterine infection causes neuroinflammation and a selective loss of immature neurons in preterm non-human primate (NHP) fetuses 3227

Abstract Description Epidemiological data strongly links fetal exposure to chorioamnionitis with adverse infant neurological outcomes, but mechanisms are unknown. We developed a NHP model of chorioamnionitis resulting in fetal inflammation without bacteremia. A microosmotic pump was surgically placed in 3 groups of R. macaque choriodecidua pocket at 85% gestation for continuous infusion of agents for 72h, followed by surgical delivery: 1) 5 Controls saline infusion 2) 5 Live uropathogenic E.coli (UTI89) infusion 3) 4 E.coli as in 2 with antibiotics starting 24h after E.coli. E.coli caused localized choriodecidua infection without microbial invasion in amniotic fluid. E.coli exposed fetuses but not controls had brain inflammation/injury in periventricular white matter, thalamus, and prefrontal cortex. Changes include: 1) Increased abundance of IBA1+ cells 2) increased presence of GFAP+ astroglia 3) selective decrease of doublecortin+ immature neurons and 4) disruption of the blood-brain barrier, suggested by morphological alterations in claudin 5 staining. Notably, antibiotic treatment did not decrease fetal neuroinflammation. Involvement of such brain areas is consistent with epidemiological associations of chorioamnionitis with cerebral palsy and behavior disorders in childhood. Our results suggest that novel anti-inflammatory interventions based on understanding molecular neuropathology may be necessary to protect the fetus from the deleterious neurological consequences of chorioamnionitis. Funding Sources Supported by U01 ES029234 (CC), Burroughs Wellcome grant (CC), CCHMC Perinatal Infection and Inflammation Collaborative (CC), R21HD90856 (SK), and R01HD 98389 (SK) Topic Categories Neuroimmunology (NEUR)