Decreased inhibition of exosomal miRNAs on SARS-CoV-2 replication underlies poor outcomes in elderly people and diabetic patients

Abstract

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks’ continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.

The role of microRNAs in solving COVID-19 puzzle from infection to therapeutics: A mini-review

“…Likewise, Wang et al (2021) analyzed serum samples of both T2D patients and elderly people and observed that the expression levels of miR-7-5p, miR-24-3p, miR-145-5p, and miR-223-3p were decreased in those individuals; however, this altered miRNA expression was not observed in young people. Since it was unveiled that both the free form and the exosome form of the aforesaid miRNAs might hinder the replication of the SARS-CoV-2 via targeting the S protein, this regulatory mechanism was negatively affected in T2D patients and elderly persons due to their low circulating levels of the miRNAs at issue; therefore, these individuals are more vulnerable to SARS-CoV-2 infection.…”

SARS-COV-2 acts as a test of Air Pollution, Lifestyle Disorders and Immune Tolerance dysregulation in human body

“…[ ] y) miR-223-3p: significantly downregulated in COVID-19 [1800]. [ ] z) miR-150-5p: significantly downregulated in COVID-19 [1637].…”

“…[ ] ac) miR-15b-5p, miR-486-3p and miR-486-5p upregulated only in severe COVID-19 patient [1627]. [ ] ad) miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p: are reported to be markedly decreased in the elderly and diabetic groups which have the capability to inhibit S protein expression and SARS-CoV-2 replication [1800]. [ ] ae) miR-17, miR-574-5p, and miR-214: are shown to induce degradation of the S glycoprotein, N and M proteins, and ORF1a of SARS-COV-2.…”

“…SARS-COV-2 is predicted to bind to miR-24 on Spike S protein and other places of the viral genome structure [1683,1465,2294]. 20. miR-24 is downregulated in severe COVID-19 patients [1800,2231]. 21.…”

“…6. As reported above SARS-COV-2 binds to miR-24 [1683,1465,2294] and also miR-24 has been found to be reduced in severe COVID-19 patients [2231,1800]. 7.…”