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Elucidating the role of SERINC5 in SARS-CoV-2 infection

阐明 SERINC5 在 SARS-CoV-2 感染中的作用

基本信息

批准号：
10372283
负责人：
Spyridon Stavrou
金额：
$ 23.93万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-18 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372283
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Adult Affect Binding Biogenesis Biological Assay COVID-19 therapeutics Cell fusion Cells Cessation of life Complex Coronavirus Coughing Data Development Drug Targeting Event Family Fever Genome Goals HIV HIV-1 Human Infection Integral Membrane Protein Integration Host Factors Malaise Maps Mediating Molecular Biology Multiple Organ Failure Mutate Mutation Names Parvovirus Persons Phosphatidylserines Play Pneumonia Protein Family Proteins Research Resources Respiratory Failure Retroviridae Retroviridae Infections Reverse Transcription Role SARS coronavirus SARS-CoV-2 antiviral SARS-CoV-2 infection SARS-CoV-2 inhibitor Series Serine Shortness of Breath Sphingolipids Surface Time Viral Viral Genome Viral Proteins Virus Virus Diseases Virus Replication antiviral drug development common symptom insight member mutant novel pandemic disease pathogenic virus receptor receptor binding targeted treatment therapeutic development therapeutic target viral entry inhibitor

项目摘要

A viral pathogen associated with severe pneumonia was recently identified as the cause of a global pandemic that has resulted in the death of over two million people. This viral pathogen was later classified as a coronavirus that was subsequently named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Currently, there is a paucity of information regarding SARS-CoV-2 infection and the cellular factors associated with it. The identification of host factors that target SARS-CoV-2 infection and the elucidation of their mechanism of action is critical for the development of SARS-CoV-2 therapeutics. It was recently shown that the Serine Incorporator (SERINC) protein family, which is comprised by 5 multipass transmembrane proteins (SERINC1-5) plays a critical role in retroviral entry, yet the role of SERINC factors on other viral infections including SARS-CoV-2 infection is currently unknown. This proposal investigates the effect of SERINC5 on SARS-CoV-2 infection. The goal of this proposal is to provide mechanistic evidence on the effect of SERINC5 on SARS-CoV-2 entry, as many times, host factors use different mechanisms to restrict viruses that belong to different viral families. Previous research has shown that human immunodeficiency virus (HIV) is potently restricted by SERINC5 in a mechanism that has not been fully elucidated. However, HIV encodes an accessory protein, Nef, which counteracts the deleterious effect of SERINC5. Similar viral proteins have been identified in other retroviruses, which demonstrates the importance of SERINC5 in retrovirus infection. Hence another aspect of this proposal is to determine a SARS-CoV-2 encoded factor that targets SERINC5 and the mechanism it utilizes to counteract SERINC5. This study will provide much needed insight into the role of a novel host factor that targets SARS- CoV-2, which is of great importance as there is not a lot of mechanistic understanding of host factors that target SARS-CoV-2. Moreover, little is known about the role of SARS-CoV-2 proteins and how they modulate the host cell; hence, the findings of this proposal will provide valuable information regarding the function of SARS-CoV-2 encoded factors. Finally, the discovery of host factors that restrict SARS-CoV-2 infection may expand the gamut of potential drug targets for the development of SARS-CoV-2 antivirals.

一种与严重肺炎相关的病毒病原体最近被确定为导致200多万人死亡的全球大流行病的原因。这种病毒病原体后来被归类为冠状病毒，随后被命名为严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）。目前，关于SARS-CoV-2感染及其相关细胞因子的研究还很缺乏，寻找靶向SARS-CoV-2感染的宿主因子并阐明其作用机制是开发SARS-CoV-2治疗药物的关键。近年来研究表明，由5个多通道跨膜蛋白（SERINC 1 -5）组成的丝氨酸蛋白酶（SERINC）家族在逆转录病毒进入细胞中起着重要作用，但SERINC因子在包括SARS-CoV-2在内的其他病毒感染中的作用目前尚不清楚。本研究旨在研究SERINC 5对SARS-CoV-2感染的影响。该提案的目的是提供SERINC 5对SARS-CoV-2进入的影响的机制证据，因为许多时候，宿主因素使用不同的机制来限制属于不同病毒家族的病毒。先前的研究表明，人类免疫缺陷病毒（HIV）是有效的限制SERINC 5的机制尚未完全阐明。然而，HIV编码辅助蛋白Nef，其抵消SERINC 5的有害作用。在其他逆转录病毒中也发现了类似的病毒蛋白，这证明了SERINC 5在逆转录病毒感染中的重要性。因此，该提议的另一方面是确定靶向SERINC 5的SARS-CoV-2编码因子及其用于抵消SERINC 5的机制。这项研究将提供急需的洞察到一个新的宿主因子的作用，靶向SARS-CoV-2，这是非常重要的，因为没有很多的机制了解宿主因子靶向SARS-CoV-2。此外，关于SARS-CoV-2蛋白的作用以及它们如何调节宿主细胞的知之甚少;因此，本提案的发现将提供关于SARS-CoV-2编码因子的功能的有价值的信息。最后，发现限制SARS-CoV-2感染的宿主因素可能会扩大SARS-CoV-2抗病毒药物开发的潜在药物靶点范围。