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

在过去几十年中，不同株冠状病毒（CoV）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大流行病（2019年）。在这一点上，没有疫苗或有效的抗病毒药物是商业上可用于这些人类病原体。CoV由四种主要的结构蛋白组成：吞噬病毒RNA的核衣壳（N）蛋白、刺突（S）蛋白、膜（M）蛋白和包膜（E）蛋白。目前，学术界和药学界的努力主要集中在参与病毒进入宿主细胞的S蛋白上，而M蛋白和E蛋白的研究较少，但显示参与病毒复制。该项目将研究来自不同CoV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COVI-19大流行的新疗法所必需的知识。除了增加有关SARS-CoV-2生物学的知识外，该项目还支持培训博士后研究员，扩大对STEM的参与。本项目将研究SARS-CoV-2和其他冠状病毒（CoV）的E蛋白，以了解这种离子通道在宿主-病毒体相互作用中的作用。多层次的方法将被用来获得全面的理解翻译后修饰的影响和不同的冠状病毒株的各种E-蛋白的序列变异性。将鉴定E蛋白的翻译后修饰模式，以确定这些修饰是否影响模型膜中E蛋白的功能。使用模型膜允许控制膜环境中的关键特征，即脂质头基的电荷和脂肪酸的饱和度，从而产生微区或非微区环境。通过使用我们独特的能力，结合联合收割机现代电子学和膜生物物理学，这些记录的吞吐量将增加。来自不同CoV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公共卫生紧急情况使得了解这种新的病原体具有紧迫的重要性。人们对这种新型冠状病毒及其与其他冠状病毒的关系知之甚少。更好地理解E蛋白在宿主-病毒体相互作用中的确切作用将非常有助于设计新的治疗方法。该RAPID奖项由BIO综合有机系统部门的生理和结构系统集群颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。该奖项反映了NSF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.