Zika virus (ZIKV) is transmitted to humans via the Aedes genus of mosquito. Following massive outbreaks of ZIKV infections in French Polynesia in 2013/14 and subsequently in Brazil in 2015, the World Health Organization (WHO) issued a Public Health Emergency of International Concern (Feb, 2016) based on the link between ZIKV and infants born with a spectrum of neurological insults including microcephaly and CNS lesions. Targeting of the fetal CNS is of major significance and concern due to the devastating outcome of microcephaly and the potential for sub-clinical yet significant impacts on the fetal CNS in the absence of microcephaly that could result in cognitive, behavioral and other CNS disorders. The olive baboon's (Papio anubis) similarity to humans in terms of genetics, brain development, placentation, size and immunology makes the baboon an excellent translational model for studies on ZIKV infection during pregnancy. Our research team has flavivirus experience, including ZIKV, in baboons. We complement this with expertise in neurobiology, maternal-fetal medicine and physiology necessary to accomplish our aims. The Oklahoma Baboon Research Resource provides us access to the needed numbers of timed-pregnant baboons to complete our aims. Our overarching hypothesis is that maternal ZIKV infection at different stages of gestation (first, second or third trimester) will result in different degrees of fetal CNS pathological phenotypes, the most severe arising from early gestation infection. Specific Aim 1- Analyze the fetal brain at 170dG (~term) to determine the effect of prolonged ZIKV infection performed at 50, 90 and 150dG (days gestation). Specific Aim 2: Analyze the fetal brain at 14 d post inoculation at early (50dG), mid (90dG) and late (150dG) gestation. We will also assess the maternal and fetal immune, inflammatory responses, viremia, fetal growth and placental pathology and function (umbilical blood flow) in response to ZIKV to relate timing of ZIKV infection and degree of inflammatory response to fetal outcome. The findings will provide essential data in a relevant non-human primate on the fetal outcome of ZIKV.

R21NS103772

2017-07-01

2020-06-30