Genetic evolution, pathogenesis and immune responses in mother to child transmission of ZIKV

抽象/总结

Abstract/Summary Our group of investigators has been collaborating over the last two years to describe the clinical aspects and pathogenesis of in utero transmission of ZIKA virus (ZIKV) infection. We have embarked in a strong collaborative effort to document and understand the pathogenesis of ZIKV. We have available to us a unique prospective cohort of well characterized ZIKV-infected mother-infant pairs who have been followed since the antenatal period, with infants now between 12 to 24 months of age and specimens collected over time. We propose to characterize ZIKV humoral immune responses over time in our cohort of mother-infant pairs who became infected during the Rio de Janeiro 2015/16 epidemic, in order to determine the timing of development of immune responses to ZIKV in perinatally infected infants, and possible correlation with intermittent viral shedding. We plan to evaluate whether infant immune responses are associated with the breadth and potency of maternal immunologic responses to ZIKV over time. To do so we will measure neutralizing antibody activity in 100 mother-infant pairs over 3 years and explore potential associations with annual infant neurodevelopmental assessments and timing of infection in gestation. We will also investigate genetic viral evolution in their ZIKV isolates and are presently sequencing whole ZIKV genome from mother-infant pairs from the same cohort who had adverse pregnancy outcomes, normal pregnancy outcomes, recurrent or relapsing infections, while also checking whether there is variability in viral sequences by compartment (CSF, blood, urine, placenta). We are also evaluating specific ZIKV-immune responses at the cellular and molecular levels and determining mechanisms by which the virus evades host immune responses during pregnancy. Our findings will answer important questions pertaining to the mechanisms of immune pathogenesis and intrinsic virologic factors associated with ZIKV mother-to-child transmission which may be predictive of longer term infant outcomes. Our well characterized population of mother-infant pairs with detailed clinical follow-up and specimens collected over time allows us to perform state of the art translational studies to elucidate mechanisms of viral pathogenesis.