Discussion
We have successfully identified VDFs that are important for SARS-CoV-2 to establish a productive virus replication (Figure 7), and their annotated functions were correlated with clinical manifestation and complications of SARS-CoV-2 infection. Increasing evidence support the association between COVID-19 and cardiovascular and renal-related diseases (Camm and Camm, 2020; Yang et al., 2020). These observations were also in line with the RNAi screening results, in which the functional annotation of some enriched VDFs and their biological pathways were also linked to the regulation of cardiac and renal functions. In fact, pathway analysis of VDFs showed ∼70% of significantly affected biological pathways are related to cardiac diseases (pink; Figure 2D). The most affected biological pathway is related to cardiac arrhythmias, which is often observed in SARS-CoV-2-infected patients, especially in critically ill cases (Figure 2D) (Babapoor-Farrokhran et al., 2020; Karamchandani et al., 2020; Rav-Acha et al., 2020). Besides, we also identified three significantly affected renal disease-related pathways (brown; Figure 2D), which is in line with the high incidence of acute kidney injury reported in SARS-CoV-2-infected cases (Yang et al., 2020). A previous study also reported the presence of coronavirus-like particles in >75% kidney biopsies of deceased SARS-CoV-2 patients (Su et al., 2020). Furthermore, PANTHER pathway analysis of the enriched VDFs identified vasopressin-related pathways as the top-affected molecular pathways (Figure 2E). The important roles of these vasopressin-related VDFs in SARS-CoV-2 infection were further validated by performing knockdown experiment (Figure 2F). Previous studies showed that vasopressin can induce differentiation of stem cells into cardiomyocytes and promote heart muscle homeostasis (Yasin et al., 1994). It can also control tonicity of body fluids by converting to arginine vasopressin (AVP) that can further regulate the arterial blood pressure (Demiselle et al., 2020). Consistently, due to their regulatory roles in maintaining homeostasis of kidney and heart, dysregulated expressions of vasopressin and AVP were also directly linked to the development of renal failure and cardiovascular system diseases (Czarzasta et al., 2018). Therefore, further investigation of the identified VDFs involved in cardiac and renal disease development may provide mechanistic insights into SARS-CoV-2-induced extrapulmonary diseases.
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