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

项目总结

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.