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.