Sex-Dependent Regulation of Host Factors Influencing SARS-CoV-2 Infection and COVID-19 Disease

项目摘要 COVID-19是由SARS-CoV-2病毒引起的疾病，通常表现为肺炎， 严重影响进展为急性呼吸窘迫综合征（ARDS）。值得注意的是，男性似乎在 COVID-19导致严重或致命结局的风险显著更高，男性特异性偏斜也 与相关冠状病毒SARS-CoV和MERS一起观察。X染色体富含免疫相关的 基因，并且女性（XX）比男性（XY）产生更强的免疫应答。x染色体失活 (XCI)使性别之间的基因剂量效应正常化，我们以前发现免疫细胞 具有新的和动态的XCI机制，允许从失活的基因特异性转录激活， X（Xi）以细胞类型特异性方式。值得注意的是，我们的初步数据表明，XCI的调节，在肺泡 2型（AT 2）细胞，SARS-CoV-2在肺中的主要靶点，也是肺中关键参与的细胞类型。 病毒损伤后的修复，在免疫细胞中看到的表型复制。因此，我们将测试新的假设 X连锁基因，包括免疫基因和ACE 2，以谱系特异性方式逃避XCI， 女性对COVID-19的相对抵抗力（目标1）。我们将检验我们的小说人性化的假设 ACE 2小鼠对SARS-CoV-2感染易感，将表现出性别差异， 老年小鼠的病理学（目的2）。总之，这些研究将进一步加深我们对 使男性易患COVID-19疾病，并将揭示降低疾病严重程度的新策略。

Project Summary COVID-19, the disease caused by the SARS-CoV-2 virus, commonly presents as pneumonia, with those most severely affected progressing to Acute Respiratory Distress Syndrome (ARDS). Notably, males seem to be at significantly higher risk for severe or fatal outcomes from COVID-19, and male-specific skewing was also observed with related coronaviruses SARS-CoV and MERS. The X chromosome is enriched for immunity-related genes, and females (XX) mount stronger immune responses than do males (XY). X-chromosome Inactivation (XCI) normalizes the gene dosage effect between the sexes and we have previously found that immune cells have novel and dynamic XCI mechanisms that allow for gene-specific transcriptional activation from the inactive X (Xi) in a cell-type specific manner. Notably, our preliminary data suggest the regulation of XCI in lung alveolar type 2 (AT2) cells, the predominant target of SARS-CoV-2 in the lung and a cell type critically involved in lung repair following viral injury, phenocopies that seen in immune cells. As such, we will test the novel hypothesis that X-linked genes, including immune genes and ACE2, escape XCI in a lineage-specific fashion and contribute to the relative resistance of females to COVID-19 (Aim 1). We will test the hypothesis that our novel humanized ACE2 mice, which are susceptible to SARS-CoV-2 infection, will exhibit sex differences with resulting lung pathologies in aged mice (Aim 2). Together, these studies will further our understanding of the mechanisms that predispose males to COVID-19 disease and will reveal novel strategies to reduce disease severity.