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

摘要/概要 在过去的两年里，我们的研究小组一直在合作描述临床方面， ZIKA病毒（ZIKV）感染的子宫内传播的发病机制。我们已经踏上了一条强大的 共同努力来记录和理解ZIKV的发病机制。我们有一个独特的 自2011年以来， 产前阶段，婴儿现在年龄在12至24个月之间，并随着时间的推移收集标本。我们 我们建议在我们的母婴配对队列中表征ZIKV体液免疫应答随时间的变化， 在里约热内卢2015/16流行期间感染，以确定发展时间 围产期感染婴儿对ZIKV的免疫应答，以及与间歇性病毒感染的可能相关性。 脱落我们计划评估婴儿免疫反应是否与免疫的广度和效力有关。 母亲对ZIKV的免疫反应。为此，我们将测量中和抗体活性 在100对3岁以上的母婴对中， 神经发育评估和妊娠期感染时间。我们还将研究遗传病毒 他们的ZIKV分离株的进化，目前正在测序来自母婴对的整个ZIKV基因组。 来自同一队列的不良妊娠结局、正常妊娠结局、复发或 复发性感染，同时还检查隔室的病毒序列是否存在变异性（CSF， 血液、尿液、胎盘）。我们还在细胞和分子水平评估特异性ZIKV免疫应答。 水平和决定机制的病毒逃避宿主的免疫反应在怀孕期间。我们 这些发现将回答有关免疫发病机制和内在免疫机制的重要问题。 与ZIKV母婴传播相关的病毒学因素，这可能是长期的预测 婴儿的结果。我们对母婴配对人群进行了详细的临床随访， 随着时间的推移收集的标本使我们能够进行最先进的翻译研究，以阐明 病毒致病机制。

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.