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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的本行政补充申请的中心重点是确定详细的分子机制 COVID-19中雌激素依赖性性别差异有助于开发急需的新型疗法以控制疫情。 2019 年冠状病毒病 (COVID-19) 的爆发已成为全球大流行病其仍未得到遏制。我们之前发表过一篇经典文章来认识性别差异首次发布 COVID-19，记录男性比女性更容易感染 COVID-19，而且更常见发展出更严重的疾病和更高的死亡率（Cai H，《柳叶刀呼吸医学》，2020 年 4 月，引文：549 截至 22 年 1 月 22 日）。这一重要的观察结果已被其他文献进一步证实。性别差异研究表明，在 COVID-19 患者中观察到的这一现象可能与男性吸烟率较高有关与较高的病毒受体 ACE2 水平相关。然而，我们发现 ACE2 和 TMPRSS2 的蛋白水平暴露于吸烟提取物（CSE）的内皮细胞中的这些变化没有变化。否则观察到的情况更糟吸烟的 COVID-19 患者的结果可能与以下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可能是不太严重的基础女性疾病，并且短期雌激素给药可能被用作该疾病的强有力的治疗选择 COVID-19 的治疗，尤其是男性和绝经后女性。这得到了强有力的初步数据的支持我们的最新出版物表明 SARS-CoV-2 刺突蛋白（S 蛋白）和白细胞介素 6 (IL-6) 刺激内皮细胞 NADPH 氧化酶亚型 2 (NOX2) 激活和氧化应激，以及病毒的上调受体 ACE2 和炎症蛋白 MCP-1 均通过雌激素治疗（氧化还原生物学，2021 年 8 月）。 S 蛋白对 NOX2 和 MCP-1 的上调是由 ACE2 的激活介导的，因为用中和抗体阻断 ACE2 能够消除反应。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阶段，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着缓解，有效降低疾病严重程度和死亡。当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 蛋白通过废除 p22phox 和 p47phox 诱导体内 ALI/ARDS 和多器官损伤 NOX2 的依赖性激活和 netrin-1 信号传导的激活。 2) 识别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，使新的治疗靶点的发现。总体而言，机械化程度高、综合性好毫无疑问，目标将揭示新的与性别差异相关的 COVID-19 分子机制，其目标将是促进开发迫切需要控制毁灭性大流行的创新疗法。