Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor

The emergence of novel betacoronaviruses has posed significant financial and human health burdens, necessitating the development of appropriate tools to combat future outbreaks. In this study, we have characterized a human cell line, IGROV-1, as a robust tool to detect, propagate, and titrate betacoronaviruses SARS-CoV-2 and HCoV-OC43. IGROV-1 cells can be used for serological assays, antiviral drug testing, and isolating SARS-CoV-2 variants from patient samples. Using time-course transcriptomics, we confirmed that IGROV-1 cells exhibit a robust innate immune response upon SARS-CoV-2 infection, recapitulating the response previously observed in primary human nasal epithelial cells. We performed genome-wide CRISPR knockout genetic screens in IGROV-1 cells and identified Aryl hydrocarbon receptor (AHR) as a critical host dependency factor for both SARS-CoV-2 and HCoV-OC43. Using DiMNF, a small molecule inhibitor of AHR, we observed that the drug selectively inhibits HCoV-OC43 infection but not SARS-CoV-2. Transcriptomic analysis in primary normal human bronchial epithelial cells revealed that DiMNF blocks HCoV-OC43 infection via basal activation of innate immune responses. Our findings highlight the potential of IGROV-1 cells as a valuable diagnostic and research tool to combat betacoronavirus diseases.

新型β冠状病毒（betacoronavirus）的出现带来了沉重的经济与人类健康负担，亟需开发合适的工具以应对未来的疫情暴发。本研究将人细胞系IGROV-1鉴定为一种可用于检测、增殖并滴定β冠状病毒SARS-CoV-2与HCoV-OC43的稳定可靠工具。IGROV-1细胞可应用于血清学检测、抗病毒药物筛选，以及从患者样本中分离SARS-CoV-2变异株。通过时间进程转录组学分析，我们证实IGROV-1细胞在感染SARS-CoV-2后会产生强烈的天然免疫应答，重现了此前在原代人鼻上皮细胞中观察到的应答模式。我们在IGROV-1细胞中开展了全基因组CRISPR敲除遗传筛选，鉴定出芳香烃受体（Aryl hydrocarbon receptor, AHR）是SARS-CoV-2与HCoV-OC43二者共同依赖的关键宿主因子。使用AHR的小分子抑制剂DiMNF，我们观察到该药物可选择性抑制HCoV-OC43的感染，但对SARS-CoV-2并无作用。对原代正常人支气管上皮细胞的转录组学分析显示，DiMNF通过介导天然免疫应答的基础激活阻断HCoV-OC43的感染。本研究结果凸显了IGROV-1细胞作为对抗β冠状病毒疾病的极具价值的诊断与研究工具的潜力。