Infant Immunologic and Neurologic Development following Maternal Infection in Pregnancy during Recent Epidemics

摘要/摘要 2019年新出现的冠状病毒病(新冠肺炎)的大规模爆发使全球迅速 传播，导致大流行感染和史无前例的全球卫生紧急情况。只是 几年前，我们目睹了寨卡病毒(ZIKV)对世界上未出生的胎儿的毁灭性影响 美洲。这项建议回应了需要填补在理解 孕期寨卡病毒和SARS-CoV-2感染等产前感染的临床影响 通过对细胞和免疫系统的评估，对其婴儿发育中的免疫系统的影响 母体感染后体液免疫反应与临床和神经发育结局 这一脆弱人群的免疫激活(MIA)。我们的研究团队一直在 在过去的7年中合作确定了子宫内胚胎的临床和细胞效应 寨卡病毒的传播，收集了数百名母亲的样本- 来自巴西的婴儿配对。我们报告了婴儿的多种产科和临床结局。 先天性寨卡病毒感染的文献中，包括寨卡病毒垂直传播率至少是 65%，感染儿童不会产生ZIKV特异性中和抗体，尽管早期 免疫球蛋白反应，母体体液免疫反应往往较强 中和活性。在新冠肺炎大流行期间，我们建立了一个母婴队列 在加州大学洛杉矶分校和里约热内卢菲奥克鲁斯的配对和控制母婴双胞胎登记到 在两个地方都有约会。我们正在利用现有的基础设施和开发的科学方法 在ZIKV疫情之后，进一步评估临床、细胞体液和 炎性参数预测暴露于病毒的婴儿和儿童的免疫结局 母体ZIKV和SARS Cov2感染。拟议研究的主要目标是 全面描述MIA对婴儿免疫发育和临床的影响 结果，重点是免疫发病机制。我们包括了200名母亲的纵向队列- 新冠肺炎的婴儿配对和美国和巴西的100对健康对照母婴 巴西200对ZIKV母婴和100对健康对照 来实现这些目标。这项RO1建议评估MIA对婴儿的影响- 存在和免疫发育。最先进的技术被用来解决科学目标， 由免疫学、传染病和先天性疾病领域的专家领导的研究 拥有持续成功、富有成效的合作伙伴关系的感染者。呈现的数据将是 了解产前感染病毒的儿童人群的免疫发病机制 曝光。

Abstract/Summary The massive outbreak of newly emerged coronavirus disease 2019 (COVID-19) saw rapid global spread, leading to a pandemic infection and an unprecedented global health emergency. Just years before, we witnessed the devastating impact of Zika virus (ZIKV) to unborn fetuses in the Americas. This proposal responds to the need to fill critical gaps in the understanding of the clinical repercussions of antenatal infections such as ZIKV and SARS-CoV-2 infection in pregnant women to the developing immune system of their infants, through the evaluation of cellular and humoral immune responses and clinical and neurodevelopmental outcomes following maternal immune activation (MIA) in this vulnerable population. Our team of researchers has been collaborating over the last 7 years to characterize the clinical and cellular effects of in utero transmission of Zika virus (ZIKV), with the collection of specimens from over hundreds of mother- infant pairs from Brazil. We reported on multiple obstetrical and clinical outcomes of infants with congenital ZIKV infection in the literature, including that ZIKV vertical transmission rate is at least 65%, that infected children do not develop ZIKV specific neutralizing antibodies despite an early IgM response, and that maternal humoral immune responses tend to be robust with highly neutralizing activity. During the COVID-19 pandemic we established a cohort of mother-infant pairs at UCLA and Fiocruz, Rio de Janeiro and controls with mother-infant dyads enrolled to date in both places. We are utilizing the existing infrastructure and scientific methods developed in the aftermath of the ZIKV epidemic to further evaluate clinical, cellular humoral and inflammatory parameters predicting immunologic outcomes in infants and children exposed to either maternal ZIKV and SARS Cov2 infection. The main goal of the proposed research is to comprehensively characterize repercussions of MIA on infant immune development and clinical outcomes, with a focus on immune pathogenesis. We include a longitudinal cohort of 200 mother- infant pairs with COVID-19 and 100 healthy control mother-infant pairs in the US and Brazil and 200 mother-infant pairs with ZIKV in Brazil and 100 healthy control pairs at the same clinical sites to address these goals. This RO1 proposes to evaluate the repercussions of MIA on infant well- being and immune development. State of the art technology is used to address the scientific aims, with the research led by experts in the field of immunology, infectious diseases & congenital infections who have ongoing successful, productive partnerships. The data rendered will be crucial for the knowledge of immune pathogenesis in pediatric populations with antenatal viral exposures.