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

摘要/摘要 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和 寨卡病毒宫内传播的发病机制我们已经踏上了一个强大的 共同努力记录和了解寨卡病毒的致病机理。我们有一款独一无二的 预期队列特征良好的ZIKV感染母婴对，自 产前阶段，现在的婴儿年龄在12到24个月之间，随着时间的推移收集样本。我们 建议在我们的母婴对队列中描述随时间推移的ZIKV体液免疫反应 在2015/16年里约热内卢疫情期间被感染，以确定发展的时机 围产期感染婴儿对ZIKV的免疫应答及其与间歇性病毒的可能相关性 正在脱落。我们计划评估婴儿的免疫反应是否与广度和效力有关 随着时间的推移，孕妇对ZIKV的免疫应答。为此，我们将测量中和抗体的活性。 在超过3年的100对母婴中，探索与年度婴儿的潜在关联 神经发育评估和妊娠期感染的时间。我们还将研究遗传病毒 他们ZIKV分离株的进化，目前正在对母婴对ZIKV全基因组进行测序 来自同一队列中有不良妊娠结局、正常妊娠结局、复发或 复发感染，同时还按间隔检查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上评估特定的ZIKV免疫反应 怀孕期间病毒逃避宿主免疫反应的水平和确定机制。我们的 这些发现将回答与免疫发病机制和内在机制有关的重要问题。 与ZIKV母婴传播相关的病毒学因素可能预示着更长期的 婴儿结局。我们的母婴配对人群具有良好的特点，具有详细的临床随访和 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来阐明 病毒致病机制的研究。

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.