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

影响 SARS-CoV-2 感染和 COVID-19 疾病的宿主因素的性别依赖性调节

基本信息

批准号：
10451255
负责人：
Montserrat C Anguera
金额：
$ 24.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451255
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Affect Age Alveolar Angiotensin II CD4 Positive T Lymphocytes COVID-19 COVID-19 morbidity COVID-19 mortality COVID-19 severity COVID-19 susceptibility COVID-19 treatment Cells Code Coronavirus Data Development Disease Disease Outbreaks Disease Outcome Disease Progression Disease model Elements Endothelial Cells Epigenetic Process Estrogen Therapy Estrogens Exhibits Fatal Outcome Female Future Gene Dosage Genes Genetic Gonadal Steroid Hormones Hormonal Hormone Responsive Hormones Human Hybrids Immune Immune response Immunity Infection Inflammatory Inflammatory Response Injury Integration Host Factors Link Lung Middle East Respiratory Syndrome Morbidity - disease rate Mus Outcome Pathology Pathway interactions Pattern Peripheral Phenocopy Pneumonia Population Predisposition Pulmonary Pathology Regulation Regulatory Element Resistance SARS coronavirus SARS-CoV-2 infection Severity of illness Sex Bias Sex Differences Signal Transduction Supplementation System Testing Transcript Transcriptional Activation Transgenic Mice Type 2 Angiotensin II Receptor Vascular Diseases Viral Virus Virus Diseases Wild Type Mouse Woman X Chromosome X Inactivation age related aged burden of illness cell type coronavirus disease cytokine high risk insight lung repair macrophage male men mortality mouse model novel novel coronavirus novel strategies post SARS-CoV-2 infection preservation prevent promoter receptor respiratory response severe COVID-19 sex transcriptome sequencing

项目摘要

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.

项目概要 COVID-19 是由 SARS-CoV-2 病毒引起的疾病，通常表现为肺炎，其中最常见的是严重影响进展为急性呼吸窘迫综合征（ARDS）。值得注意的是，男性似乎处于 COVID-19 导致严重或致命后果的风险显着更高，而且男性特有的倾向也观察到相关冠状病毒 SARS-CoV 和 MERS。 X染色体富集与免疫相关基因，并且女性（XX）比男性（XY）产生更强的免疫反应。 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颖且动态的 XCI 机制，允许从非活性状态进行基因特异性转录激活 X (Xi) 以细胞类型特定的方式。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 在肺部的主要靶标，也是与肺部密切相关的细胞类型病毒损伤后的修复，免疫细胞中看到的表型。因此，我们将检验这个新假设 X连锁基因，包括免疫基因和ACE2，以谱系特异性方式逃避XCI并做出贡献女性对 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易受 SARS-CoV-2 感染的 ACE2 小鼠将表现出性别差异，从而导致肺部感染老年小鼠的病理学（目标 2）。总之，这些研究将进一步加深我们对机制的理解。男性更容易患上 COVID-19 疾病，并将揭示降低疾病严重程度的新策略。