Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses,Cell

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Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses
Cell ( IF 45.5 ) Pub Date : 2020-12-09 , DOI: 10.1016/j.cell.2020.12.004
Ruofan Wang ₁ , Camille R Simoneau ₂ , Jessie Kulsuptrakul ₁ , Mehdi Bouhaddou ₃ , Katherine A Travisano ₁ , Jennifer M Hayashi ₄ , Jared Carlson-Stevermer ₅ , James R Zengel ₆ , Christopher M Richards ₆ , Parinaz Fozouni ₇ , Jennifer Oki ₅ , Lauren Rodriguez ₈ , Bastian Joehnk ₉ , Keith Walcott ₉ , Kevin Holden ₅ , Anita Sil ₉ , Jan E Carette ₆ , Nevan J Krogan ₃ , Melanie Ott ₄ , Andreas S Puschnik ₁

Affiliation

Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA.
Synthego Corporation, Menlo Park, CA 94025, USA.
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
UCSF CoLabs, Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.

中文翻译：

基因筛选识别 SARS-CoV-2 和普通感冒冠状病毒的宿主因素

冠状病毒科是导致人类疾病的病毒家族，范围从轻度呼吸道感染到可能致命的急性呼吸窘迫综合征。找到多种冠状病毒共有的宿主因素可以促进治疗方法的开发，以对抗当前和未来的冠状病毒大流行。在这里，我们对感染 SARS-CoV-2 以及两种季节性流行的普通感冒冠状病毒 OC43 和 229E 的细胞进行了全基因组 CRISPR 筛选。这种方法正确地识别了不同的病毒进入因子 ACE2（对于 SARS-CoV-2）、氨肽酶 N（对于 229E）和糖胺聚糖（对于 OC43）。此外，我们确定磷脂酰肌醇磷酸盐生物合成和胆固醇稳态是支持所有三种冠状病毒感染的关键宿主途径。相比之下，溶酶体蛋白 TMEM106B 似乎是 SARS-CoV-2 感染所特有的。磷脂酰肌醇激酶的药理学抑制和胆固醇稳态降低了所有三种冠状病毒的复制。这些发现为理解冠状病毒生命周期和开发宿主导向疗法提供了重要见解。

更新日期：2021-01-07

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