Molecular mechanisms of sex difference in COVID-19 enabling novel therapeutics

COVID-19性别差异的分子机制促成新疗法

• 批准号: 10555078
• 负责人: Hua Linda Cai
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555078
• 关键词: ACE2; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Administrative Supplement; Attenuated; Autopsy; Biological Assay; Biology; CCL2 gene; COVID-19 outbreak; COVID-19 patient; Cell membrane; Cells; Cessation of life; Chronic; Data; Development; Diagnostic; Disease; Disease Outbreaks; Endothelial Cells; Endothelium; Epithelial; Estrogen Therapy; Estrogens; Evans blue stain; Exposure to; Female; Functional disorder; Genes; Heart; High Prevalence; Infection; Inflammation; Inflammatory; Injury; Innovative Therapy; Interleukin-6; K-18 conjugate; Kidney; Link; Literature; Lung; MAPK3 gene; MYLK gene; Mediating; Medicine; Methodology; Molecular; Multiple Organ Failure; Mus; NADPH Oxidase; NTN1 gene; Organ failure; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Patients; Permeability; Postmenopause; Production; Protein Isoforms; Proteins; Publications; Publishing; Pulmonary Edema; RNA Sequences; Regulation; Reporting; Research; Respiratory Disease; Role; SARS-CoV-2 spike protein; Serine Protease; Severity of illness; Sex Differences; Signal Pathway; Signal Transduction; Smoker; Smoking; Structure of parenchyma of lung; Superoxides; Systems Biology; TMPRSS2 gene; Therapeutic; Time; Uncertainty; Up-Regulation; Viral; Virus Diseases; Virus Receptors; Weight; Woman; calmodulin-dependent protein kinase II; cell injury; cell type; cigarette smoking; cytokine; cytokine release syndrome; effective therapy; endothelial dysfunction; experimental study; gender difference; gene network; lung injury; male; men; mortality; multiorgan injury; neutralizing antibody; new therapeutic target; novel; novel therapeutics; pandemic disease; preservation; respiratory; response; single-cell RNA sequencing; transcriptome sequencing; vaccine development; virus infection mechanism

ABSTRACT The central focus of this Administrative Supplement application to is to identify detailed molecular mechanisms of estrogen-dependent sex difference in COVID-19 to enable development of novel therapeutics that are in urgent need to control the pandemic. The outbreak of coronavirus disease 2019 (COVID-19) has become a worldwide pandemic that has remained uncontained. We have previously published a classical article to recognize sex difference of COVID-19 for the first time, documenting that males are more susceptible to COVID-19 than females, and more often to develop more severe disease with higher mortality (Cai H, Lancet Respiratory Medicine, April 2020, Citation: 549 by 01/22/22). This important observation has been further confirmed by additional literatures. The gender difference observed in COVID-19 patients is potentially linked to higher prevalence of cigarette smoking in men that was shown to be associated with higher viral receptor ACE2 levels. However, we found that protein levels of ACE2 and TMPRSS2 were not changed in endothelial cells exposed to cigarette smoking extract (CSE). The otherwise observed worse outcomes in COVID-19 patients who are smokers, is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesize that estrogen mediated protection might however underlie less severe disease in females, and that short term estrogen administration might be used as a robust therapeutic option for the treatment of COVID-19, especially in men and postmenopausal women. This is supported by strong preliminary data and our latest publication indicating that SARS-CoV-2 spike protein (S protein) and interleukin-6 (IL-6) stimulated endothelial cell NADPH oxidase isoform 2 (NOX2) activation and oxidative stress, as well as upregulation of viral receptor ACE2 and inflammatory protein MCP-1, were all substantially attenuated by estrogen treatment (Redox Biology, Aug 2021). The upregulation in NOX2 and MCP-1 by S protein is mediated by activation of ACE2 since blockage of ACE2 with neutralizing antibody was able to abrogate the responses. These data indicate that oxidative stress and endothelial dysfunction triggered by initial viral infection (S protein), and by cytokine storm (IL-6) at later stage, which represent major pathological features of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS)/multi-organ failure, can all be remarkably alleviated by estrogen to effectively reduce disease severity and mortality. The current project aims to address two specific aims: 1) To examine whether estrogen treatment alleviates SARS-CoV-2 S protein induced ALI/ARDS and multi-organ injuries in vivo via abrogation of p22phox and p47phox- dependent activation of NOX2 and activation of netrin-1 signaling. 2) To identify and validate novel genes and gene pathways/networks regulated by S protein and estrogen with a special focus on netrin-1 signaling, enabling discoveries of novel therapeutic targets. Overall, accomplishments of both of highly mechanistic and well-integrated aims will no doubt reveal novel sex difference related molecular mechanisms of COVID-19, targeting of which would facilitate development of innovative therapies urgently in need to control the devastating pandemic.

摘要 本行政补充申请的中心重点是确定详细的分子机制， COVID-19中的雌激素依赖性性别差异，以开发迫切需要的新疗法 来控制疫情2019冠状病毒病（COVID-19）爆发已成为全球大流行病 尚未得到控制我们以前发表过一篇经典文章，认识到性别差异， COVID-19首次，记录了男性比女性更容易感染COVID-19， 发展为更严重的疾病，死亡率更高（Cai H，Lancet Respiratory Medicine，2020年4月，引文：549 01/22/22）。这一重要的观察结果得到了其他文献的进一步证实。性别差异 在COVID-19患者中观察到的结果可能与男性吸烟率较高有关， 与较高的病毒受体ACE 2水平有关。然而，我们发现ACE 2和TMPRSS 2的蛋白水平 在暴露于香烟烟雾提取物（CSE）的内皮细胞中没有改变。否则观察到的更差 吸烟的COVID-19患者的结局可能与基线呼吸系统疾病相关， 长期吸烟。相反，我们假设雌激素介导的保护作用可能是不那么严重的基础， 女性的疾病，短期雌激素给药可能被用作一个强大的治疗选择， 治疗COVID-19，尤其是男性和绝经后女性。这得到了有力的初步数据的支持 我们最新的研究表明，SARS-CoV-2刺突蛋白（S蛋白）和白细胞介素-6（IL-6）刺激了 内皮细胞NADPH氧化酶亚型2（NOX 2）激活和氧化应激，以及病毒 受体ACE 2和炎性蛋白MCP-1，均被雌激素处理显著减弱（Redox 生物学，2021年8月）。S蛋白对NOX 2和MCP-1的上调是由ACE 2的激活介导的， 用中和抗体阻断ACE 2能够消除应答。这些数据表明， 由初始病毒感染（S蛋白）和随后细胞因子风暴（IL-6）触发的应激和内皮功能障碍 期，代表急性肺损伤（ALI）/急性呼吸窘迫综合征的主要病理特征 （ARDS）/多器官衰竭，都可以通过雌激素显著缓解，以有效降低疾病严重程度， mortality.目前的项目旨在解决两个具体的目标：1）检查雌激素治疗是否会导致 SARS-CoV-2S蛋白通过抑制p22 phox和p47 phox基因表达诱导ALI/ARDS和多器官损伤 NOX 2的依赖性激活和netrin-1信号传导的激活。2)鉴定和验证新基因和基因 由S蛋白和雌激素调节的通路/网络，特别关注netrin-1信号传导， 发现新的治疗靶点。总的来说，两者的成就都是高度机械化和良好的集成 这些目标无疑将揭示新的COVID-19性别差异相关的分子机制， 促进急需的创新疗法的开发，以控制这一毁灭性的大流行病。