Diffuse neuroinflammation and immature neuron loss in fetal Rhesus macaques after short-term intrauterine infection.

Chorioamnionitis or infection of the amniotic fluid and membranes surrounding the fetus can cause fetal systemic inflammation and adverse neurological outcomes. To investigate the pathogenesis of chorioamnionitis-induced neurological injury, we developed a non-human primate model by infusion of live Escherichia coli. A micro-osmotic pump was placed in pregnant Rhesus macaques at ~ 85% term gestation via hysterotomy. Live E. coli (105 CFU/h, 1µL/h, n = 7) or sterile broth (Controls, 1µL/h, n = 7) infusions were given over 72 h followed by necropsy. A third group of pregnant macaques received microbicidal antibiotics 24 h after the start of E. coli infusion (n = 5). Amniotic fluid, cord plasma, and fetal brain regions were carefully preserved for comparative analysis of fetal systemic and brain inflammation. E. coli exposure caused fetal systemic inflammation without bacteremia and induced pro-inflammatory cytokines in the periventricular white matter (PVWM) and thalamus. A diffuse inflammation characterized by aberrant proliferation and activation of IBA1+ microglia and GFAP+ astrocytes was observed in multiple brain regions. There was a selective vulnerability of the DCX expressing immature neurons with relative sparing of cortical mature neurons expressing MAP2 or NeuN. Periventricular and entorhinal white matter regions were particularly vulnerable with relative sparing of the cortex. These pathogenic changes of fetal brain injury were observed after 72 h exposure. Maternal antibiotics cleared the bacteremia but did not decrease neuroinflammation or neuropathology. These results highlight the potential need for anti-inflammatory adjunctive therapy in addition to antibiotics for optimal outcomes in chorioamnionitis.