Cellular microRNAs target SARS-CoV-2 spike protein and restrict viral replication, 2023, Vaddadi et al.

[SNT Gatchaman]

Cellular microRNAs target SARS-CoV-2 spike protein and restrict viral replication
Kishore Vaddadi ; Chaitanya Gandikota ; Chaoqun Huang ; Yurong Liang ; Lin Liu

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and are implicated in viral replication and host tropism. miRNAs can impact the viruses either by directly interacting with the viral genome or modulating host factors. Although many miRNAs have predicted binding sites in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral RNA genome, little experimental validation has been done.

We first identified 492 miRNAs that have binding site(s) on the spike (S) viral RNA by a bioinformatics prediction. We then validated the selected 39 miRNAs by examining S-protein levels after co-expressing the S-protein and a miRNA into the cells. Seven miRNAs were found to reduce the S-protein levels more than 50%. Among them, miR-15a, miR-153, miR-298, miR-508, miR-1909 and miR-3130 also significantly reduced SARS-CoV-2 viral replication. SARS-CoV-2 infection decreased the expression levels of miR-298, miR-497, miR-508, miR-1909, and miR-3130, but had no significant effects on miR-15a and miR-153 levels. Intriguingly, the targeting sequences of these miRNAs on the S viral RNA showed sequence conservation among the variants of concern.

Our results suggest that these miRNAs elicit effective antiviral defense against SARS-CoV-2 by modulating S-protein expression and are likely targeting all the variants. Thus, the data signifies the therapeutic potential of miRNA-based therapy for SARS-CoV-2 infections.

Link | PDF (American Journal of Physiology-Cell Physiology)

 

[SNT Gatchaman]

Host miRNAs can act as antiviral factors by interfering with viral infection and replication. In the present study, we identified six miRNAs that suppressed SARS-CoV-2 replication by targeting S-protein

We further validated the S-protein-targeting ability of the predicted miRNAs by analyzing S-protein expression in miRNA overexpressing cells. Among them, miRNA-15a, miR-153, miR-298, miR-497, miR-508, miR-1909, miR-3130 decreased S-protein expression by more than 50%. Out of the seven S-protein suppressing miRNAs, six miRNAs, miR-15a, miR-153, miR-298, miR-508, miR-1909, and miR-3130, showed a significant reduction in SARS-CoV-2 replication

Previous studies have shown that circulating exosomal miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) that are decreased in elder and diabetic people, inhibit SARS-CoV-2 replication by directly targeting the S-protein. Interestingly, the S-protein-targeting miRNAs - miR-15a, miR-298, miR-508, miR-1909, miR-3130, and miR-145 in our study can also circulate as extracellular miRNAs.

In this study, we showed that SARS-CoV-2 infection reduced the endogenous levels of miR-298, miR-508, miR-497, miR-1909, and miR-3130, but not miR-15a and miR-153, suggesting that the changes in host miRNA expression is not due to host shutoff effects after SARS-CoV-2 infection. Other studies also showed the downregulation of miRNAs in virus infections such as miR-15a-5p in SARS-CoV-2-infected patient samples* and miR-3130 in Kaposi’s sarcoma-associated herpes virus infection.

Altered expression of miRNAs upon virus infection could be a consequence of virus strategy to subvert miRNA-mediated inhibition either by interfering with miRNA biogenesis** or increasing their degradation to support its growth. Based on our results, we speculate that SARS-CoV-2 may overcome the miRNA-mediated antiviral restriction by suppressing the miRNA levels.

* Referencing Expression of plasma IFN signaling-related miRNAs during acute SARS-CoV-2 infection and its association with RBD-IgG antibody response (2021, Virology Journal)
** See also thread Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA (2022)