Zika virus (ZIKV) has been identified as a neuroteratogen similar to the TORCH agents cytomegalovirus (CMV) and rubella. Neurotropic teratogenic viruses such as CMV cause a wide range of sequelae in the infected human fetus and infant, yet we have little definitive information about the range of outcomes related to congenital Zika syndrome. These questions are difficult to study, largely due to the rapid emergence of Zika virus and our incomplete understanding of the virus's natural history and mechanisms of pathogenesis. However, our previous research on congenital CMV in the rhesus monkey model offers a precedent and template for improved appreciation of Zika virus pathogenic outcomes, and for the rational design of diagnostic, preventative, and interventional strategies for this rapidly spreading global teratogen. The studies in this proposal capitalize on our considerable expertise with the rhesus CMV (RhCMV) in utero infection model, which defined the pathology associated with disease and has been used to investigate the safety of new vaccines and protective interventions. It has become increasingly apparent that environmental factors such as infectious teratogens and inflammation together exert a persistent or even lifelong impact on neurodevelopment and immune function. The objectives of these studies include the following Specific Aims: (1) Determine the fetal immunologic effects of placental ZIKV and test if immune activation is associated with the extent of central nervous system (CNS) infection, neural precursor cell loss, and brain malformations. In these investigations we will test the hypothesis that Zika virus infection results in maternal cell ingress, alteration of decidual cytokine production, increased microchimerism, and fetal/neonatal systemic inflammation. (2) Evaluate the impact of neonatal ZIKV infection on immune activation, immune ontogeny, and neurodevelopment. In these studies we will test the hypothesis that in neonates, Zika virus infection has a significant correlated influence on immune function and neurodevelopment. Overall, these investigations will provide new insights into the developmental perturbations resulting from Zika virus infection, and will leverage our experiences in developing outcome metrics and interventions that can protect the fetus and infant from the devastating consequences of congenital disease.
These studies focus on the interface of Zika virus infection with development of the brain and immune system. Investigations will explore prenatal and early postnatal events that shape neurodevelopmental outcomes in infected fetuses and infants.
