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

项目总结/摘要 自2020年SARS-CoV-2出现以来，在疟疾流行的撒哈拉以南非洲地区， 都受到了SARS-CoV-2感染的影响。2010年期间SARS-CoV-2和疟疾合并感染的高发病率 随着新的SARS-CoV-2变异体的出现并在随后的几波中引起再次感染，怀孕将继续下去。 SARS-CoV-2和妊娠期疟疾都与不良的出生和婴儿结局有关，包括 早产，低出生体重，生长和神经发育受损-可能通过 母体炎症妊娠期SARS-CoV-2对高度疟疾患者长期发育影响的数据 暴露人群缺乏。为了解决这一差距，我将利用来自母婴配对的样本和数据 参加了两个补充正在进行的NIH资助的抗疟疾化学预防试验在布西亚，乌干达。在 在妊娠试验中，孕妇被随机分配到三种抗疟疾化学预防方案之一， 这些妇女所生的婴儿在一项单独的临床试验中被随机分配， 抗疟疾化学预防或安慰剂，并随访至4岁。这些审判与乌干达的 早期SARS-CoV-2激增，初步数据表明， 怀孕使用正在进行的试验中收集的临床数据和样本，我将检验以下假设： 妊娠期暴露于SARS-CoV-2的婴儿在幼儿期的生长和神经发育将受损 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， 两种病原体的协同炎症作用。在目标1中，我将对储存的血浆样本进行血清学检测 回顾性识别在怀孕期间经历SARS-CoV-2的母亲，并比较 4岁以下妊娠期有或无SARS-CoV-2暴露的婴儿。在目标2中，我将比较 患有和未患有妊娠期SARS-CoV-2的婴儿在24个月和42个月时的神经认知测试得分。 在目标3中，我将探索妊娠期SARS-CoV-2的母体蛋白质组免疫特征，并确定 妊娠期SARS-CoV-2对婴儿生长和神经发育的影响是由特异性的 炎症通路。这个队列是唯一准备解决SARS-CoV-2在怀孕中的影响， 疟疾流行背景下，在SARS-CoV广泛基线之前收集纵向数据和样本， 2豁免权。为了实现这些目标，并成为一个独立的翻译研究员在热带围产期 感染，我已经组建了一个跨学科的导师团队，专家在传染病，产科， 儿科学、神经心理学、免疫学和全球健康。这项拟议研究的结果立即 这对改善高危婴儿的护理具有重要意义，并可能为未来确定诊断或治疗目标。 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.