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 这项行政补充申请的中心焦点是确定详细的分子机制 新冠肺炎中雌激素依赖性的性别差异使迫切需要的新疗法的开发 来控制大流行。2019年冠状病毒病暴发(新冠肺炎)已成为世界性大流行 这一点仍未得到遏制。我们之前发表了一篇经典文章，以认识性别差异 新冠肺炎首次发现，男性比女性更易患新冠肺炎，而且更常见 发展为更严重的疾病，死亡率更高(蔡H，柳叶刀呼吸医学，2020年4月，引文：549 到1/22/22)。这一重要的观察结果已被更多的文献进一步证实。性别差异 在新冠肺炎患者中观察到的风险可能与男性吸烟的更高患病率有关，这一结果显示 与较高的病毒受体ACE2水平有关。然而，我们发现ACE2和TMPRSS2的蛋白水平 香烟烟雾提取物(CSE)对血管内皮细胞无明显影响。在其他方面观察到的情况更糟 新冠肺炎吸烟者的预后可能与与以下疾病相关的基线呼吸道疾病有关 长期吸烟。相反，我们假设雌激素介导的保护作用可能不那么严重。 女性的疾病，短期服用雌激素可以作为一种强有力的治疗选择 新冠肺炎的治疗，尤其是对男性和绝经后女性。强劲的初步数据支持了这一点 而我们最新发表的研究表明，SARS-CoV-2刺激蛋白(S蛋白)和白细胞介素6(IL-6)可刺激 内皮细胞NADPH氧化酶亚型2(NOX2)的激活和氧化应激以及病毒的上调 受体ACE2和炎性蛋白MCP-1都被雌激素治疗(氧化还原)显著减弱 生物学，2021年8月)。S蛋白通过激活血管紧张素转换酶2上调一氧化氮合酶2和单核细胞趋化蛋白1 用中和抗体阻断ACE2可使上述反应消失。这些数据表明，氧化 最初的病毒感染(S蛋白)和后来的细胞因子风暴(IL-6)引发的应激和内皮功能障碍 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，雌激素均可显著缓解，有效降低疾病严重性和 死亡率。目前的项目旨在解决两个具体目标：1)检查雌激素治疗是否可以缓解 SARS-CoV-2 S蛋白通过抑制p22Phox和p47Phox诱导ALI/ARDS及体内多器官损伤 依赖于NOX2的激活和Netrin-1信号的激活。2)鉴定和验证新基因和新基因 受S蛋白和雌激素调控的通路/网络，特别关注Netrin-1信号，使 新的治疗靶点的发现。总体而言，既有高度机械化的成就，又有良好整合的成就 AIMS无疑将揭示与新冠肺炎性别差异相关的新的分子机制，其靶向将 促进迫切需要的创新疗法的开发，以控制毁灭性的大流行。