Development of a NHP model for determining the causal relationship between Zika virus infection during pregnancy and fetal microcephaly.

Research project

Description

SUMMARY 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-Barré 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.
StatusActive
Effective start/end date9/20/168/31/18

Funding

  • National Institutes of Health: $262,500.00

Fingerprint

Microcephaly
Primates
Pregnancy
Zika Virus Infection
Mothers
Viruses
Macaca mulatta
Disease Outbreaks
Brain
Placental Insufficiency
Pacific Ocean
Flavivirus
Aptitude
Viral RNA
Adaptive Immunity
Virus Diseases
Amniotic Fluid
Pregnancy Outcome
Fetal Development
Innate Immunity