A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance.
A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance.
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DOI：
10.7554/elife.69719
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发表时间：
2021-08-17
期刊：
影响因子：
7.7
通讯作者：
Dunham I
中科院分区：
文献类型：
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作者：
Anisul M;Shilts J;Schwartzentruber J;Hayhurst J;Buniello A;Shaikho Elhaj Mohammed E;Zheng J;Holmes M;Ochoa D;Carmona M;Maranville J;Gaunt TR;Emilsson V;Gudnason V;McDonagh EM;Wright GJ;Ghoussaini M;Dunham I
病毒 SARS-CoV-2 可以利用易感宿主的生物脆弱性（例如宿主蛋白），从而导致严重的 COVID-19 的发展。为了识别可能导致严重 COVID-19 风险的宿主蛋白，我们利用公开的蛋白质和 COVID-19 数据集进行了蛋白质组范围的遗传共定位测试以及多基因（泛）和顺式孟德尔随机化分析。我们的分析方法确定了几个已知的目标（例如 ABO、OAS1），但也提名了新的蛋白质，例如可溶性 Fas（共定位概率 >0.9，p=1 × 10-4），表明 Fas 介导的细胞凋亡是 COVID-19 风险的潜在目标。多基因（泛）和顺式孟德尔随机化分析显示，基因预测的 ABO 蛋白与多种 COVID-19 表型之间存在一致的关联。 ABO 信号是高度多效性的，对与 ABO 信号相关的蛋白质的查找显示最强的关联是与可溶性 CD209。我们通过实验证明 CD209 直接与 SARS-CoV-2 的刺突蛋白相互作用，这提出了一种可以解释 ABO 与 COVID-19 关联的机制。我们的工作提供了 SARS-CoV-2 可能利用的宿主靶标的优先列表，并且是进一步研究 CD209 和 FAS 作为 COVID-19 治疗上易于处理的靶标的先驱。 MAK、JSc、JH、AB、DO、MC、EMM、MG、ID 由 Open Targets 资助。 J.Z.和 T.R.G 由英国医学研究委员会综合流行病学部门 (MC_UU_00011/4) 资助。 JSh 和 GJW 由 Wellcome Trust Grant 206194 资助。本研究部分由 Wellcome Trust [Grant 206194] 资助。出于开放获取的目的，作者已对由此提交的任何作者接受的手稿版本应用了 CC BY 公共版权许可。感染导致 COVID-19 的病毒的个人可能会出现多种症状。这些症状的范围从无症状或轻微症状到严重疾病和死亡。已知关键的人口统计因素，例如年龄、性别和种族，会影响个人对感染的易感性。然而，分子因素，例如独特的基因突变和基因表达水平，也可以通过影响体内蛋白质的水平对患者的反应产生重大影响。蛋白质过于丰富或过于稀缺可能意味着死于 COVID-19 或幸存的差异。识别宿主中影响病毒如何感染个体、逃避免疫防御或引发严重疾病的分子因素，可以为治疗 COVID-19 患者提供新方法。即使病毒突变成新毒株，这些因素也可能保持不变。因此，这些见解可能适用于所有病毒株，包括当前的病毒株，例如α和δ，以及未来可能出现的任何新病毒株。 Karim 等人使用这种“自然实验”方法。比较了 30,000 多名 COVID-19 患者和 100 万健康人的基因图谱。研究发现 9 种蛋白质对 COVID-19 感染和疾病严重程度有影响。四种蛋白质被列为潜在治疗目标的首要任务。一种名为 CD209（也称为 DC-SIGN）的蛋白质与病毒如何进入宿主细胞有关，并且是与 COVID-19 关系最密切的蛋白质之一。两种蛋白质，即 IL-6R 和 FAS，参与免疫反应，可能是导致严重 COVID-19 中常见的免疫过度激活的原因。最后，一种名为 OAS1 的蛋白质构成了人体先天抗病毒防御系统的一部分，似乎可以降低对 COVID-19 的易感性。更多地了解影响 COVID-19 严重程度的蛋白质，为预测、保护和治疗可能对感染产生严重或致命反应的患者开辟了新方法。事实上，最近的临床试验已经针对其中一种已鉴定的蛋白质 (IL-6R) 进行了靶向治疗，并取得了一些令人鼓舞的结果。将 CD209 视为该病毒的潜在受体可以为治疗提供另一种途径，类似于之前阻止病毒与受体蛋白已知相互作用的成功方法。最终，这项研究可以提供一套全新的治疗方案，以帮助对抗 COVID-19 大流行。
The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a ‘natural experiment’ approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body’s innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus’ known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic.