Maternal obesity and inflammation as drivers of maternal morbidity in COVID-19

项目总结 虽然怀孕期间新冠肺炎上的大量关注一直集中在是否垂直 发生传播，新冠肺炎还与严重的孕产妇发病率和孕产妇有关 死亡率。妊娠特异性免疫变化如何影响对SARS-CoV-2和 新冠肺炎疾病的发展轨迹尚不清楚。同样，人们也不知道母体肥胖、 这是最普遍的母体合并症之一，影响严重疾病的风险。近期工作 提示重症新冠肺炎的细胞因子风暴病理生理机制可能由单核细胞介导。 和巨噬细胞。我们实验室对母亲肥胖及其对促炎性疾病的影响的关注 因此，孕期巨噬细胞的启动使我们能够很好地回答这些紧迫的科学问题 问题。鉴于最近的预测，数百万孕妇将接触新冠病毒- 19、了解孕期严重疾病的发病机制是一个紧迫的公共卫生问题 担忧。 “母体肥胖的胎脑-胎盘免疫激活”是一种临床前R01，用于测试 母体肥胖与胎儿脑小胶质细胞炎症启动相关的假说 胎盘巨噬细胞或霍夫鲍尔细胞是子代认知的靶向机制 赤字。资助项目的一个关键翻译方面是确定霍夫鲍尔细胞 代表了母体肥胖背景下胎儿脑小胶质细胞反应性的一种新的生物替代物。 这项行政补充提案旨在测试一个以母亲为中心的假说，该假说基于 同样的前提：母亲肥胖会增强母亲对SARS-CoV-2的炎症反应 通过启动母体单核细胞和胎盘巨噬细胞对病毒的过度反应而感染，以及 孕妇外周血单核细胞和胎盘Hofbauer细胞反应性可作为一种风险 新冠肺炎病情严重程度的评估或生物标志物。在这里，我们提议扩大体外细胞 目标1a中的刺激实验，包括对SARS-CoV-2暴露和未暴露的刺激 人外周血单核细胞与Toll样受体配基结合，并检测对其影响 肥胖对母体单核细胞对SARS-CoV-2的影响。我们还建议扩大单元格 AIM 1b的RNA测序实验包括暴露和未暴露的人Hofbauer细胞 SARS-CoV-2和母亲肥胖，以确定这些暴露是否会导致促炎 霍夫鲍尔细胞程序的改变。总而言之，这些实验将产生关于如何 母体肥胖和母体单核细胞和胎盘巨噬细胞的相关启动可能推动 新冠肺炎背景下的孕产妇发病率。单核细胞-巨噬细胞启动不仅可用于 确定有发病风险的妇女，但这是可以为新疗法提供信息的有针对性的机制。

PROJECT SUMMARY While substantial attention on COVID-19 in pregnancy has been focused on whether vertical transmission occurs, COVID-19 is also associated with severe maternal morbidity and maternal mortality. How pregnancy-specific immune changes impact the response to SARS-CoV-2 and the trajectory of COVID-19 illness remains unknown. Similarly, it is not understood how maternal obesity, one of the most widespread maternal comorbidities, influences risk for severe disease. Recent work suggests that the cytokine storm pathophysiology of severe COVID-19 may be mediated by monocytes and macrophages. Our laboratory’s focus on maternal obesity and its impact on pro-inflammatory macrophage priming in pregnancy therefore positions us well to answer these pressing scientific questions. In light of the recent projection that millions of pregnant women will be exposed to COVID- 19, understanding mechanisms underlying severe disease in pregnancy is an urgent public health concern. “Fetal Brain-Placental Immune Activation in Maternal Obesity” is a pre-clinical R01 that tests the hypothesis that maternal obesity-associated inflammatory priming of fetal brain microglia and resident placental macrophages or Hofbauer cells is a targetable mechanism underlying offspring cognitive deficits. A key translational aspect of the funded project is to determine whether Hofbauer cells represent a novel biologic surrogate for fetal brain microglial reactivity in the setting of maternal obesity. This administrative supplement proposal aims to test a maternally-focused hypothesis based on the same premise: that maternal obesity will potentiate maternal inflammatory response to SARS-CoV-2 infection by priming maternal monocytes and placental macrophages to overrespond to the virus, and that maternal peripheral monocyte and placental Hofbauer cell reactivity can be used as a risk assessment or biomarker for COVID-19 disease severity. Here we propose to expand the ex vivo cell stimulation experiments in Aim 1a to include stimulation of SARS-CoV-2-exposed and unexposed human maternal peripheral monocytes with toll-like receptor ligands, and to examine the impact of obesity on maternal monocyte response to SARS-CoV-2. We also propose to expand the single-cell RNA-sequencing experiments in Aim 1b to include human Hofbauer cells exposed and unexposed to SARS-CoV-2 and maternal obesity, to determine whether these exposures induce pro-inflammatory alterations in Hofbauer cell programs. Together, these experiments will generate key insights into how maternal obesity and associated priming of maternal monocytes and placental macrophages may drive maternal morbidity in the setting of COVID-19. Monocyte-macrophage priming can be used not only to identify women at risk for morbidity, but are targetable mechanisms that can inform novel therapies.