Zika virus (ZIKV) is a Flavivirus that has recently emerged in the Western hemisphere as a major viral pathogen. The virus was discovered in 1947 and the majority of ZIKV-associated diseases were considered to be mild. However, the recent outbreak, as well as the preceding outbreaks in the South Pacific Ocean region has been associated with an increased number of neurological sequellae including Guillian-Barr Syndrome. The most notable increase in pathogenesis has been the ZIKV infection of pregnant women and associated developmental abnormalities observed in the fetus including microcephaly. Zika viral RNA has been detected in pregnant mothers, the fetal brain as well as amniotic fluid. ZIKV infections during pregnancy have been associated with an increased prevalence of placental insufficiency and intra-uterine growth restriction. However, the mechanisms of causation of these pathologies between maternal ZIKV infections to the clinical adverse neonatal neurological outcomes have yet to be defined. In addition, how the timing of virus infection during pregnancy affects these outcomes is still unknown. We have developed a nonhuman primate model of ZIKV infection in 5 adult rhesus monkeys including 3 females. We have determined the optimal viral dosage and characterized viral distribution, innate and adaptive immunity and clinical outcomes. One important finding is that the virus remains persistent in tissues including those of the female reproductive tract. We are also currently characterizing the infection of one pregnant Rhesus macaque, which has demonstrated dramatic changes in placental blood flow and a relative decrease in fetal brain size. We hypothesize that maternal ZIKV infection during pregnancy negatively impacts utero-placental perfusion and initiates a fetal and placental inflammatory response that contributes to the development of microcephaly and other aberrations of fetal development. The goal of this project is determine whether the timing of ZIKV infection during fetal gestation (1st, 2nd or 3rd trimesters) affects the ability of the virus to cause fetal developmental abnormalities. Utilizing our unique non-human primate (NHP) catheterized pregnancy model in conjunction with state-of-the art MRI and ultrasonography, our multidisciplinary team of investigators will further our understanding of the pathogenesis of ZIKV infection during pregnancy and the severity of fetal neurological injury.
The goal of this project is to establish a non-human primate model of Zika virus infection of pregnant animals to identify the causes of Zika virus-associated effects on fetal development including microcephaly. Zika virus is an emerging viral pathogen in the Americas and an area of significant concern. The proposed model will be useful for determining the mechanisms of the negative impact that Zika virus infection of pregnant women has on the developing fetus, as well as for future testing of vaccine and therapeutics directed against the virus to protect the developing neonate.
| Dudley, Dawn M; Van Rompay, Koen K; Coffey, Lark L et al. (2018) Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med 24:1104-1107 |
| Hirsch, Alec J; Roberts, Victoria H J; Grigsby, Peta L et al. (2018) Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Commun 9:263 |
| Hirsch, Alec J; Smith, Jessica L; Haese, Nicole N et al. (2017) Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog 13:e1006219 |
