Dysregulated host miRNAs with antiviral potential against SARS-CoV-2 identified from COVID-19 patients

MicroRNAs (miRNAs) are small RNA molecules implicated in controlling most cellular processes by either deadenylating/degrading mRNA transcripts or inhibiting their translation. Viruses and their hosts utilize miRNAs for regulating gene expression, targeting both cellular and viral mRNAs. Since the onset of the COVID-19 pandemic, numerous studies have aimed at elucidating the role of host responses at the molecular and cellular levels in determining disease severity among infected individuals. However, the precise interactions between SARS-CoV-2 and host miRNAs, and their biological impact on virus replication or pathogenesis remains poorly understood. Employing miRNAseq and real time PCR, we have previously identified dysregulated host miRNAs in a large cohort of SARS-CoV-2 infected individuals. In this study, we used specialized bioinformatic and computational tools, as well as 3D docking analysis to investigate the ability of the dysregulated miRNAs observed in these COVID-19 patients to target the SARS-CoV-2 genome. Our analyses reveal that some of the differentially regulated, COVID-19-specific miRNAs had the potential to directly target the SARS-CoV-2 genome or its sub-genomic transcripts essential for virion formation, viral replication, and infection. These included mRNAs for non-structural and structural proteins, suggesting that SARS-CoV-2 may benefit from these miRNAs for its replication or immune evasion. Further miRNA target gene analysis revealed how these miRNAs may also target host cellular pathways, including FoxO, AMPK, mTOR, PI3-Akt, and ErbB, essential for critical cellular functions. Interestingly, these pathways are also disrupted during conditions like diabetes, aging, and neurodegenerative disorders, as well as frequently exploited by viruses to enhance virus replication and pathogenesis. In summary, this work identifies several endogenous host miRNAs dysregulated during SARS-CoV-2 infection that can be exploited to not only target the virus itself, but also mitigate severe disease during future pandemic(s) with any SARS-CoV-2 variant-of-concern (VOC). Thus, it offers promising new potential molecular targets for therapeutic development, complementing existing antiviral strategies. Coupled with identification of cellular pathways involved in pathogenesis, these findings underscore the profound impact of miRNAs on viral pathogenesis, host metabolism, and immune responses.