Gene ablation using CRISPR/Cas9 showed that both DDX58 and IFIH1 sense severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection in human embryonic kidney HEK293T cells (Kouwaki T et al. 2021). Similar findings were reported for SARS-CoV-2-infected human adenocarcinoma-derived lung epithelial Calu-3 cells (Thorne LG et al. 2021). On the contrary, several studies showed that depletion of DDX58 had no effect in infected Calu-3 cells (Sampaio NG et al. 2021; Yin X et al. 2021; Rebendenne A et al. 2021). Another group reported that the helicase domain of DDX58 interacts with the 3′ UTR of the SARS-CoV-2 RNA in human lung epithelial cells, though this interaction failed to activate the ATPase activity of DDX58 and binding to MAVS (Yamada T et al. 2021). DDX58 (RIG-I), along with other proteins associated to virus infection (MAVS, TRAFs), were differentially expressed in COVID-19 patients vs healthy controls (Leng L et al. 2020). This Reactome event describes binding of DDX58 (RIG-I) to SARS-CoV-2 dsRNA intermediates, however the role of DDX58 in the antiviral innate immune response to SARS-CoV-2 remains elusive.