SARS-CoV-2 Nsp13 helicase modulates miR-146a-mediated signaling pathways

Despite the successful development of vaccines and antiviral therapeutics against SARS-CoV-2, its tendency to mutate rapidly has emphasized the need for continued research to better understand this virus's mechanism of pathogenesis and interactions with host signaling pathways. In this study, we sought to explore how the SARS-CoV-2 non-structural protein 13 (Nsp13) helicase, a highly conserved coronavirus protein that is essential for viral replication, influences host biological and cellular processes. Global transcriptomic analyses of Nsp13-transfected A549 cells identified changes in pathways involved in post-transcriptional gene silencing and translational repression by RNA, such as microRNAs (miRNAs). Upon further bioinformatic analyses, we identified miR-146a-mediated signaling pathways to be of interest as this miRNA has been previously linked to the regulation of host inflammation and innate immune responses. We found that miR-146a was induced in Nsp13-transfected cells and observed a corresponding decrease in the gene expression of two miR-146a targets, TRAF6 and IRAK1, which are important upstream regulators of NF-kB activation and IFN signaling. These results suggest that Nsp13-induced miR-146a signaling cascades, namely NF-kB activation and SMAD4 signaling, may provide valuable insight for the development of novel antiviral therapeutics against COVID-19 variants.