Molecular mapping of SARS-CoV2 and the host response with multiomics mass spectrometry to stratify disease outcomes

该项目是了解新冠肺炎在全球人口中的发病机制的国际努力的一部分。尽管在基因水平上对SARS-CoV-2病毒有了相当深入的了解，但病毒结构的关键方面及其致病作用仍有待确定。同样，有助于疾病进展的分子描述符定义得很差，在测试策略中还没有考虑到。质谱学(MS)可以在分子水平(多组学)上提供快速、准确和可重复性的诊断信息，补充基因组信息。在这个项目中，我们将使用MS来描述患者对新冠肺炎的反应(来自英国国民健康保险制度合作伙伴的样本)。这项研究将被我们的工业项目合作伙伴用于诊断/预后测试方案以及疫苗和治疗的开发。研究将构成由PI，新冠肺炎MS(目前在28个国家的600多名成员)发起的国际联盟中的英国努力，他们同意分享经验、协议、材料和数据。这种新一代测量方法既可转移又可访问，通过涉及多个合作实验室的复制研究，我们将克服当前基于实验室的方法的准确性和敏感性问题，同时还向新冠肺炎提供有关个人风险的总体数据。与目前采用的间接实验室方法不同，我们的多重组学方法可以使用固有的物理属性-质量-来提供病毒的详细结构信息及其对宿主的影响。产出是多方面的：我们将改进测试方法，分层治疗选项，确定隔离要求，并将急需的速度引入新的治疗开发计划的测量方面-针对新冠肺炎和未来威胁。通过我们在生物标记物发现和验证方面的专业知识，以描述疾病机制，我们拥有处理管道，以从数据中提取最大程度的理解。作为蛋白质结构分析的世界领先者，我们将从结构上描述病毒：细胞相互作用，为疫苗设计和治疗干预提供信息。所获得的知识将可转化为医院检测实验室进行靶向分析，生物制药公司用于疫苗和治疗开发，以及用于生物标记物或血清学测试的试剂的开发和质量控制。与LGC有限公司的诊断和测量公司(Waters、Thermo、Sciex、Bruker)以及通过CAMS的分析和测量科学社区(辉瑞、阿斯利康、葛兰素史克和艾尔建)合作，我们将能够扩大我们的方法并将结果转化为向NHS提供有针对性的分析以用于生物标记物、验证血清学测试以及嵌入未来弹性的疫苗和治疗开发。这项国际努力是有目的地在地理上传播的，允许地区NHS实验室进入，以实现快速实施。最后，我们建立了新冠肺炎MS联盟，以共享样本处理协议，并使所有经过精心挑选的数据集公开并可供全球抗击这种疾病的努力使用。

This project forms part of an international level effort to understand the mechanisms of COVID-19 disease in the global population. Despite the considerable insight gained into the virus,SARS-CoV-2, at the genetic level, the key facets of the virus structure and its pathogenic effects remain to be determined. Equally molecular descriptors that contribute to disease progression are poorly defined, and have not yet been considered in testing strategies. Mass spectrometry (MS) can provide rapid, precise and reproducible diagnostic information at the molecular level (multiomics) that complements genomic information. In this project we will use MS to profile patient response to COVID-19 (with samples from NHS partners). This research will be exploited by our industrial project partners for diagnostic/prognostic testing protocols and for the development of vaccines and therapeutics. Research will constitute the UK effort in an international coalition initiated by the PI, COVID-19 MS, (currently over 600 members in 28 countries) who have agreed to share experience, protocols, materials and data. This next generation measurement approach is both transferable and accessible and through replication studies involving multiple partner labs we will overcome the accuracy, sensitivity issues of current lab- based approaches while also providing population data about individual risk to COVID-19. Our multiomics approach allows detailed structural information of the virus and its effect on the host using an intrinsic physical property - mass - unlike the indirect lab approaches currently employed. Outputs are multifold: we will refine testing approaches, stratify treatment options, determine isolation requirements and bring much needed speed into measurement aspects of novel therapeutic development programmes - for COVID-19 and future threats.Through our expertise in biomarker discovery and validation to profile disease mechanisms we possess the processing pipelines to extract maximum understanding from the data. As world leaders in protein structure analysis, we will structurally characterise virus:cell interactions, informing vaccine design and therapeutic intervention. Knowledge gained will be translatable to hospital testing laboratories for targeted assays, to biopharmaceutical companies for vaccine and therapeutics development, and for the development and quality control of reagents for biomarker or serological tests. Working with LGC Ltd. diagnostics and measurement companies (Waters, Thermo, Sciex, Bruker) and through CAMS the Community for Analytical and Measurement Science major Pharmaceutical companies (Pfizer, AstraZeneca , GSK, and Allergan) we will be able to scale up our methods and translate the outcomes to provide targeted assays to the NHS for biomarkers, to validate serological tests and for vaccine and therapeutic development embedding future resilience. The international effort is purposefully geographically spread allowing regional NHS lab access to enable rapid implementation. Finally, we established the COVID-19 MS Coalition to share sample processing protocols and to make all curated datasets open and accessible for global effort to combat this disease.