Impact of gestational SARS-CoV-2 and maternal inflammation on child growth and neurodevelopment in a malaria-endemic setting

项目摘要/摘要 自2020年出现SARS-CoV-2以来，在疟疾流行的撒哈拉以南非洲地区，数百万名孕妇 都受到了SARS-CoV-2感染的影响。年SARS-CoV-2和疟疾混合感染率较高 随着新的SARS-CoV-2变种的出现，怀孕将继续，并在随后的几波中导致再次感染。 SARS-CoV-2和孕期疟疾都与不良分娩和婴儿结局有关--包括 早产、低出生体重以及生长和神经发育受损--可能是通过 母体炎症。高度疟疾患者孕期SARS-CoV-2的长期发育影响资料 受感染的人群很少。为了解决这一差距，我将利用母婴二人组的样本和数据 在乌干达布西亚参加了由美国国立卫生研究院资助的两项互补的正在进行的抗疟疾化学预防试验。在 怀孕试验中，孕妇被随机分成三种抗疟疾化学预防方案之一和 通过分娩进行跟踪；这些妇女所生的婴儿在一项单独的临床试验中被随机接受 抗疟疾化学预防或安慰剂，并跟踪至4岁。这些审判与乌干达的 早期SARS-CoV-2激增，初步数据显示SARS-CoV-2和疟疾在 怀孕了。使用作为正在进行的试验的一部分收集的临床数据和样本，我将检验以下假设 孕期感染SARS-CoV-2的婴儿在儿童早期会有生长和神经发育障碍 与未暴露的婴儿相比，这是由母体炎症介导的。我进一步假设 怀孕期间接触SARS-CoV-2和疟疾会增加婴儿的不良结局，这是因为 两种病原体的协同炎症作用。在目标1中，我将使用存储的血浆样本的血清学测试 对孕期感染SARS-CoV-2的母亲进行回顾性鉴定，比较孕期母亲的生长发育情况 有和没有孕期接触SARS-CoV-2的婴儿一直持续到4岁。在《目标2》中，我将比较 患有和没有感染SARS-CoV-2的婴儿在24和42个月时的神经认知测试得分。 在目标3中，我将探索怀孕期间SARS-CoV-2的母体蛋白质组免疫特征，并确定 妊娠SARS-CoV-2对婴儿生长和神经发育的影响是通过特异性介导的 炎症途径。这一队列独特地准备好应对SARS-CoV-2在怀孕期间对 疟疾流行环境，在流行基线SARS-CoV之前收集的纵向数据和样本- 2豁免权。实现这些目标，成为热带围产期的独立翻译研究人员 传染病，我组建了一个跨学科的专家导师团队，在传染病，产科， 儿科学、神经心理学、免疫学和全球卫生。这项拟议的研究的结果立即 对改善高危婴儿护理的影响，并可以确定未来的诊断或治疗目标 临床干预。

PROJECT SUMMARY / ABSTRACT Since the emergence of SARS-CoV-2 in 2020, millions of pregnancies in malaria-endemic sub-Saharan Africa have been impacted by SARS-CoV-2 infection. High rates of SARS-CoV-2 and malaria co-infections during pregnancy will continue as new SARS-CoV-2 variants emerge and cause re-infections in subsequent waves. SARS-CoV-2 and malaria in pregnancy are both associated with adverse birth and infant outcomes – including preterm birth, low birth weight, and impaired growth and neurodevelopment – possibly mediated through maternal inflammation. Data on long-term developmental effects of gestational SARS-CoV-2 in highly malaria exposed populations are lacking. To address this gap, I will leverage samples and data from mother-infant dyads enrolled in two complementary ongoing NIH-funded antimalarial chemoprevention trials in Busia, Uganda. In the pregnancy trial, pregnant women are randomized to one of three antimalarial chemoprevention regimens and followed through delivery; infants born to these women are being randomized in a separate clinical trial to receive antimalarial chemoprevention or placebo and followed to age 4 years. These trials have coincided with Uganda’s early SARS-CoV-2 surges, and preliminary data indicate high incidence of both SARS-CoV-2 and malaria during pregnancy. Using clinical data and samples collected as part of the ongoing trials, I will test the hypothesis that infants exposed to gestational SARS-CoV-2 will have impaired growth and neurodevelopment in early childhood when compared with unexposed infants, and that this is mediated by maternal inflammation. I further hypothesize that exposure to both SARS-CoV-2 and malaria in pregnancy increases adverse infant outcomes due to the synergistic inflammatory effects of both pathogens. In Aim 1, I will use serologic testing of stored plasma samples to retrospectively identify mothers who experienced SARS-CoV-2 during pregnancy and compare the growth of infants with and without gestational SARS-CoV-2 exposure through age 4 years. In Aim 2, I will compare neurocognitive test scores at ages 24 and 42 months among infants with and without gestational SARS-CoV-2. In Aim 3, I will explore maternal proteomic immune signatures of SARS-CoV-2 in pregnancy and determine if the effect of gestational SARS-CoV-2 on infant growth and neurodevelopment is mediated by specific inflammatory pathways. This cohort is uniquely poised to address the impact of SARS-CoV-2 in pregnancy in a malaria endemic setting, with longitudinal data and samples collected before widespread baseline SARS-CoV- 2 immunity. To accomplish these aims and become an independent translational researcher in tropical perinatal infections, I have assembled an interdisciplinary mentorship team of experts in in infectious diseases, obstetrics, pediatrics, neuropsychology, immunology, and global health. Results from this proposed study have immediate implications for improving care of at-risk infants, and could identify diagnostic or therapeutic targets for future clinical interventions.