RAPID: Comparative functional characterization of strain-specific CoV E-proteins and involvement in host-specific virulence

过去几十年，不同冠状病毒株的病毒感染导致了SARS-CoV（2003年）和MERS（2012年）流行病，以及最近的COVID-19大流行（2019年）。目前，市面上还没有针对这些人类病原体的疫苗或有效的抗病毒药物。冠状病毒由四种主要结构蛋白构成；吞噬病毒RNA的核衣壳蛋白(N)、刺突蛋白(S)、膜蛋白(M)和包膜蛋白(E)。目前，学术和制药方面的努力主要集中在参与病毒进入宿主细胞的s蛋白上，而对M蛋白和e蛋白的研究较少，但已证明它们参与病毒复制。本项目将研究不同冠状病毒株的e蛋白，以更好地了解其功能。该项目将提高我们对SARS-CoV-2的理解，这种理解是确定控制当前covid -19大流行的新疗法所必需的知识。除了增加对SARS-CoV-2生物学的了解外，该项目还支持培养博士后，扩大STEM领域的参与。本项目将研究SARS-CoV-2和其他冠状病毒（cov）的e蛋白，以了解该离子通道在宿主-病毒粒子相互作用中的作用。我们将采用多层次的方法来全面了解不同冠状病毒株中不同e蛋白的翻译后修饰和序列变异性的影响。将鉴定e蛋白翻译后修饰的模式，以确定这些修饰是否影响模型膜中e蛋白的功能。使用模型膜可以控制膜环境中的关键特征，即脂质头基团的电荷和脂肪酸的饱和，从而创建微结构域或非微结构域环境。这些记录的吞吐量将增加利用我们独特的能力，结合现代电子和膜生物物理学。来自不同冠状病毒株的e蛋白将用于确定在宿主样环境中对生产性或非生产性感染发展的影响。当前的COVID-19突发公共卫生事件使得了解这种新的病原体变得迫切重要。人们对这种新型冠状病毒及其与其他冠状病毒体的关系知之甚少。更好地了解e蛋白在宿主-病毒粒子相互作用中的确切作用将对设计新的治疗方法非常有帮助。该RAPID奖由综合有机体系统生物学部的生理和结构系统集群获得，资金来自《冠状病毒援助、救济和经济安全（CARES）法案》。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Viral infections in the last decades with different strains of the coronavirus (CoV) have led to the SARS-CoV (2003) and MERS (2012) epidemics and to the most recent COVID-19 pandemic (2019). At this point, no vaccine or effective antiviral drug is commercially available for these human pathogens. CoVs are built out of four major structural proteins; the nucleocapsid (N) protein engulfing the viral RNA, the spike (S) protein, the membrane (M) protein and the envelope (E) protein. Presently, academic and pharmaceutical efforts are mainly focused on the S-protein which is involved in the entry of the virus into the host cell, whereas the M- and E-proteins are less well studied but are shown to be involved in viral replication. This project will study the E-protein from different CoV strains to better understand its function. This project will improve our understanding of SARS-CoV-2, and this understanding is knowledge necessary to identify new therapeutics to control this current COVI-19 pandemic. In addition to increasing knowledge about SARS-CoV-2 biology, this project also supports the training of a post-doctoral fellow, broadening participation in STEM. This project will study the E-protein of SARS-CoV-2 and other coronaviruses (CoVs) to understand the role of this ion channel in host-virion interaction. A multi-level approach will be used to gain comprehensive understanding on effects of the post-translational modifications and sequence variability of various E-proteins from different CoV strains. Patterns in the post-translational modification of E-proteins will be identified to determine whether these modifications affect the functionality of the E-protein in model membranes. Using model membranes allows for control of key-features in the membrane environment, namely charge of lipid head-groups and saturation of fatty acids creating a microdomain or non-microdomain environment. The throughput of these recordings will be increased by using our unique abilities to combine modern electronics and membrane biophysics. E-proteins from different CoV strains will be used to identify the impact on the development of productive or non-productive infections in a host-like environment. The current COVID-19 public health emergency makes understanding this new pathogen of urgent importance. Little is known about this novel CoV and its relationship to other CoV virions. Understanding better the exact role that the E-protein plays in the host-virion interaction will be very helpful in devising new therapeutics. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.