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

PROJECT Summary: While substantial attention on COVID-19 in pregnancy has been focused on whether verticaltransmission occurs, COVID-19 is also associated with severe maternal morbidity and maternalmortality. How pregnancy-specific immune changes impact the response to SARS-CoV-2 and thetrajectory 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 worksuggests that the cytokine storm pathophysiology of severe COVID-19 may be mediated by monocytesand macrophages. Our laboratory's focus on maternal obesity and its impact on pro-inflammatorymacrophage priming in pregnancy therefore positions us well to answer these pressing scientificquestions. 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 healthconcern."Fetal Brain-Placental Immune Activation in Maternal Obesity" is a pre-clinical R01 that tests thehypothesis that maternal obesity-associated inflammatory priming of fetal brain microglia and residentplacental macrophages or Hofbauer cells is a targetable mechanism underlying offspring cognitivedeficits. A key translational aspect of the funded project is to determine whether Hofbauer cellsrepresent 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 thesame premise: that maternal obesity will potentiate maternal inflammatory response to SARS-CoV-2infection by priming maternal monocytes and placental macrophages to overrespond to the virus, andthat maternal peripheral monocyte and placental Hofbauer cell reactivity can be used as a riskassessment or biomarker for COVID-19 disease severity. Here we propose to expand the ex vivo cellstimulation experiments in Aim 1a to include stimulation of SARS-CoV-2-exposed and unexposedhuman maternal peripheral monocytes with toll-like receptor ligands, and to examine the impact ofobesity on maternal monocyte response to SARS-CoV-2. We also propose to expand the single-cellRNA-sequencing experiments in Aim 1b to include human Hofbauer cells exposed and unexposed toSARS-CoV-2 and maternal obesity, to determine whether these exposures induce pro-inflammatoryalterations in Hofbauer cell programs. Together, these experiments will generate key insights into howmaternal obesity and associated priming of maternal monocytes and placental macrophages may drivematernal morbidity in the setting of COVID-19. Monocyte-macrophage priming can be used not only toidentify women at risk for morbidity, but are targetable mechanisms that can inform novel therapies.