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

项目摘要 虽然人们对怀孕期间COVID-19的大量关注集中在是否垂直 传播发生时，COVID-19还与严重的孕产妇发病率和孕产妇死亡率有关。 mortality.妊娠特异性免疫变化如何影响对SARS-CoV-2的反应以及 COVID-19疾病的发展轨迹仍然未知。同样，我们也不知道母亲的肥胖， 最普遍的母亲合并症之一，影响严重疾病的风险。最近的工作 表明严重COVID-19的细胞因子风暴病理生理学可能由单核细胞介导 和巨噬细胞。我们实验室的重点是母亲肥胖及其对促炎性细胞因子的影响。 因此，在怀孕期间巨噬细胞启动使我们能够很好地回答这些紧迫的科学问题。 问题.根据最近的预测，数百万孕妇将暴露于COVID-19， 19，了解妊娠期严重疾病的潜在机制是一项紧迫的公共卫生问题 关心 “孕妇肥胖症中胎儿大脑-胎盘免疫激活”是一项临床前R 01，测试了 母亲肥胖与胎儿脑内小胶质细胞炎症启动和居民 胎盘巨噬细胞或Hofbauer细胞是后代认知的潜在靶向机制 赤字该资助项目的一个关键转化方面是确定霍夫鲍尔细胞是否 代表了一种新的生物替代胎儿脑小胶质细胞反应性的母亲肥胖的设置。 这一行政补充提案旨在检验一个以母亲为中心的假设， 同样的前提：母亲肥胖会增强母亲对SARS-CoV-2的炎症反应 通过引发母体单核细胞和胎盘巨噬细胞对病毒过度反应而感染，以及 母体外周血单核细胞和胎盘Hofbauer细胞的反应性可以作为一种风险， 评估或生物标志物的COVID-19疾病的严重程度。在这里，我们建议扩大离体细胞 目标1a中的刺激实验包括SARS-CoV-2暴露和未暴露的刺激 人母体外周血单核细胞与Toll样受体配体，并检查的影响， 肥胖对母体单核细胞对SARS-CoV-2反应的影响我们还建议扩大单细胞 Aim 1b中的RNA测序实验包括暴露和未暴露于以下物质的人Hofbauer细胞： SARS-CoV-2和母亲肥胖，以确定这些暴露是否会诱导促炎性反应。 Hofbauer细胞程序的改变总之，这些实验将产生关键的见解， 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导致 COVID-19背景下的孕产妇发病率。单核细胞-巨噬细胞引发不仅可用于 确定妇女的发病风险，但有针对性的机制，可以告知新的治疗方法。

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.