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

项目摘要 新冠肺炎是由SARS-CoV-2病毒引起的疾病，通常表现为肺炎，最常见的 严重影响进展为急性呼吸窘迫综合征(ARDS)。值得注意的是，雄性似乎在 新冠肺炎导致严重或致命后果的风险显著增加，男性特有的倾斜也是 用相关冠状病毒SARS-CoV和MERS观察。X染色体富含免疫相关物质 基因，雌性(XX)比雄性(XY)安装更强的免疫反应。X染色体失活 (XCI)使性别之间的基因剂量效应正常化，我们之前发现免疫细胞 具有新的和动态的XCI机制，允许从不活跃的基因特异性转录激活 X(Xi)以特定于细胞类型的方式。值得注意的是，我们的初步数据表明，XCI在肺泡中的调节 2型(AT2)细胞，SARS-CoV-2在肺中的主要靶点，也是一种与肺密切相关的细胞类型 病毒损伤后的修复，免疫细胞中的表型复制。因此，我们将检验新的假设 X连锁基因，包括免疫基因和ACE2，以一种谱系特有的方式逃避XCI，并在 女性对新冠肺炎的相对抵抗力(目标1)。我们将检验这样一个假设：我们的小说人性化了 容易感染SARS-CoV-2的ACE2小鼠的肺部将表现出性别差异 老龄小鼠的病理学(目标2)。总之，这些研究将进一步加深我们对 使男性易患新冠肺炎病，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.