RNAi screening using HK-2 cells: insights into the roles of soluble ACE2 in SARS-CoV-2 infection. Yeung et al

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line—HK-2—that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screening and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection. Importantly, we discovered an overlooked role of a secretory form of SARS-CoV-2 receptor, soluble angiotensin converting enzyme 2 (sACE2), in SARS-CoV-2 infection. Further investigations revealed that SARS-CoV-2 exploits receptor-mediated endocytosis through interaction between its spike with sACE2 or sACE2-vasopressin via AT1 or AVPR1B, respectively. Our identification of new VDFs and the regulatory effect of sACE2 on SARS-CoV-2 infection shed new insights into pathogenesis and cell entry mechanism of SARS-CoV-2 as well as potential treatment strategies for COVID-19.严重急性呼吸综合征冠状病毒2（Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）可引发急性呼吸道疾病与多器官衰竭。探寻SARS-CoV-2感染所必需的人类宿主因子，有助于推动治疗策略的制定。本研究选用对SARS-CoV-2高度易感的人肾细胞系HK-2，开展全基因组RNA干扰筛选，鉴定出病毒依赖因子（virus dependency factors, VDFs），这类因子在与SARS-CoV-2感染临床表征相关的生物学通路中发挥调控作用。尤为重要的是，本研究发现了SARS-CoV-2受体的分泌型形式——可溶性血管紧张素转换酶2（soluble angiotensin converting enzyme 2, sACE2）在SARS-CoV-2感染中此前被忽视的功能。进一步研究表明，SARS-CoV-2可通过其刺突蛋白与相关分子的相互作用，借助受体介导的内吞途径实现细胞入侵：当刺突蛋白与sACE2结合时，通过AT1受体介导内吞；当刺突蛋白与sACE2-精氨酸加压素复合物结合时，则通过AVPR1B受体介导内吞。本研究对新型病毒依赖因子的鉴定，以及sACE2对SARS-CoV-2感染的调控效应，为阐明SARS-CoV-2的致病机制与细胞入侵通路提供了全新视角，同时为新型冠状病毒肺炎（COVID-19）的潜在治疗方案提供了新的研究方向。