美国耶鲁大学Craig B. Wilen、博德研究所John G. Doench等研究人员合作利用全基因组CRISPR筛选，揭示出对SARS-CoV-2感染至关重要的宿主因子。 这一研究成果于2020年10月20日在线发表在国际学术期刊《细胞》上。
研究人员在感染了SARS-CoV-2、MERS-CoV、表达SARS-CoV-1突刺的蝙蝠冠状病毒HKU5以及表达SARS-CoV-2突刺的VSV的Vero-E6细胞中进行了全基因组CRISPR筛选。研究人员确定了已知的SARS-CoV-2宿主因子，包括受体ACE2和蛋白酶组织蛋白酶L。研究人员还发现了前病毒基因和途径，包括分别为SARS谱系和泛冠状病毒特异性的HMGB1和SWI/SNF染色质重塑复合体。
研究人员发现，HMGB1调节ACE2表达，对于SARS-CoV-2、SARS-CoV-1和NL63的病毒进入至关重要。研究人员还显示，已鉴定基因产物的小分子拮抗剂抑制了猴子和人类细胞中的SARS-CoV-2感染，从而证明了这些基因突变在物种中的保守作用。这些共同确定了SARS-CoV-2的潜在治疗靶标，并揭示了SARS谱系特异性和泛冠状病毒宿主因子，这些因子可调节对高致病性冠状病毒的敏感性。
据介绍，鉴定对SARS-CoV-2感染至关重要的宿主基因可能揭示新的治疗靶点，并有助于了解COVID-19的发病机理。
附：英文原文
Title: Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection
Author: Jin Wei, Mia Madel Alfajaro, Peter C. DeWeirdt, Ruth E. Hanna, William J. Lu-Culligan, Wesley L. Cai, Madison S. Strine, Shang-Min Zhang, Vincent R. Graziano, Cameron O. Schmitz, Jennifer S. Chen, Madeleine C. Mankowski, Renata B. Filler, Neal G. Ravindra, Victor Gasque, Fernando J. de Miguel, Ajinkya Patil, Huacui Chen, Kasopefoluwa Y. Oguntuyo, Laura Abriola, Yulia V. Surovtseva, Robert C. Orchard, Benhur Lee, Brett D. Lindenbach, Katerina Politi, David van Dijk, Cigall Kadoch, Matthew D. Simon, Qin Yan, John G. Doench, Craig B. Wilen
Issue&Volume: 2020-10-20
Abstract: Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here, we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, MERS-CoV, bat coronavirus HKU5 expressing the SARS-CoV-1 spike, and VSV expressing the SARS-CoV-2 spike. We identify known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways including HMGB1 and the SWI/SNF chromatin remodeling complex that are SARS-lineage and pan-coronavirus specific, respectively. We show HMGB1 regulates ACE2 expression and is critical for viral entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. Together this identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS-lineage specific and pan-coronavirus host factors that regulate susceptibility to highly pathogenic coronaviruses.
DOI: 10.1016/j.cell.2020.10.028
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31392-1