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The role of short ACE2 in Sars-CoV-2 infection and patients susceptibility to COVID-19

短 ACE2 在 Sars-CoV-2 感染和患者对 COVID-19 易感性中的作用

基本信息

批准号：
BB/W003260/2
负责人：
Vito Mennella
金额：
$ 69.66万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW003260%2F2
关键词：
role short ACE2 Sars CoV

项目摘要

The virus responsible for COVID-19, SARS-CoV-2 utilizes a protein on the surface of cells named Angiotensin Converting Enzyme II (ACE2) as an entry gate. The presence and amount of ACE2 on specific cells is largely responsible for the ability of the SARS-CoV-2 virus to infect cells in the human body. It is therefore of critical importance to study how ACE2 levels vary in different cells and individuals, especially in categories at risk for COVID-19, to understand how this could affect their predisposition to infection and disease severity.We recently discovered that airway cells express a second form of ACE2, which we named short ACE2, in addition to the previously known, long form of ACE2. This novel short ACE2 does not appear to allow virus entry because it lacks regions involved in virus interaction. Surprisingly, we also discovered that short ACE2 is the main form produced in response to Interferons (IFNs); molecules released from cells of the immune system in response to viral infections to protect our tissues.These discoveries made clear that there is an urgent need to better understand the pattern of long and short ACE2 expression in cells and how this varies in patients. Since short ACE2 is IFNs-regulated, and it is not competent for SARS-CoV-2 entry, we reason that it might be part of a mechanism for protecting airway cells from SARS-CoV-2 infection. In this proposal we will study the levels of short and long ACE2 in different cells and patients to correctly understand the relationship between ACE2 levels and susceptibility to infection from SARS-CoV-2. In particular, we will study patients at particular risk of infection to COVID-19 such as Black, Asian and Minority Ethnic (BAME) patients, and patients with severe respiratory diseases such as COPD. To better understand the function of short ACE2 and its potential role in protecting cells from viral infection, we will generate cellular models including human airway cells lacking or having an excess of short ACE2 to investigate its effect on SARS-CoV-2 infection. This study will generate critical information about the interaction between the virus and different cell types in the lung. Importantly it will help identify why some people are more susceptible to SARS-CoV-2 and offer insight into novel therapeutic possibilities targeting short ACE-2; ones aimed at reducing viral transmission and COVID-19 disease severity.

导致COVID-19的病毒SARS-CoV-2利用细胞表面的一种名为血管紧张素转换酶II（ACE 2）的蛋白质作为进入门。特定细胞上ACE 2的存在和数量在很大程度上决定了SARS-CoV-2病毒感染人体细胞的能力。因此，研究ACE 2水平在不同细胞和个体中的变化至关重要，特别是在COVID-19风险类别中，以了解这如何影响他们对感染和疾病严重程度的易感性。我们最近发现气道细胞表达第二种形式的ACE 2，我们将其命名为短ACE 2，除了之前已知的长形式的ACE 2。这种新的短ACE 2似乎不允许病毒进入，因为它缺乏参与病毒相互作用的区域。令人惊讶的是，我们还发现，短ACE 2是响应干扰素（IFN）产生的主要形式;干扰素是免疫系统细胞响应病毒感染释放的分子，以保护我们的组织。这些发现清楚地表明，迫切需要更好地了解细胞中长ACE 2和短ACE 2的表达模式以及患者中的差异。由于短ACE 2受IFN调节，并且它不能进入SARS-CoV-2，我们推断它可能是保护气道细胞免受SARS-CoV-2感染的机制的一部分。在本研究中，我们将研究不同细胞和患者中短和长ACE 2的水平，以正确理解ACE 2水平与SARS-CoV-2感染易感性之间的关系。特别是，我们将研究特别有感染COVID-19风险的患者，如黑人、亚洲人和少数民族（BAME）患者，以及患有严重呼吸道疾病（如COPD）的患者。为了更好地了解短ACE 2的功能及其在保护细胞免受病毒感染中的潜在作用，我们将建立包括缺乏或过量短ACE 2的人气道细胞在内的细胞模型，以研究其对SARS-CoV-2感染的影响。这项研究将产生关于病毒与肺中不同细胞类型之间相互作用的关键信息。重要的是，它将有助于确定为什么有些人更容易感染SARS-CoV-2，并提供针对短ACE-2的新治疗可能性的见解;旨在减少病毒传播和COVID-19疾病严重程度的治疗。