Researchers Identify Four Human Host Exosomal miRNAs That Inhibit SARS-CoV-2

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Chinese researchers from Nanjing University, Wuhan Institute of Virology, National Center of Gerontology at Beijing Hospital and the Army Engineering University of PLA have in a new breakthrough study identified 4 human host exosomal miRNAs that possess antiviral properties and are able to inhibit the SARS-CoV-2 coronavirus.

Furthermore it was found that varying amounts of these miRNAs  and also the ‘quality’ of these miRNAs especially in the elderly could explain why different individuals manifest varying COVID-19 disease outcomes.

It has been found that older individuals 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.
 
The study team investigated whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes.
 
The study team 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.
 
The team 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.
 
 
The study findings were published in the peer reviewed journal: Nature’s  
Signal Transduction And Targeted Therapy. https://www.nature.com/articles/s41392-021-00716-y
 
Lead research Dr Chen-Yu Zhang and his study team from Nanjing University presents a rather striking finding that four circulating miRNAs, which are high in healthy people and much lower in older people and diabetic patients, could effectively inhibit SARS-CoV-2 replication by directly targeting the S protein.
 
It was found that serum exosomes containing these miRNAs from young individuals could strongly inhibit SARS-CoV-2 replication, but this inhibitory effect was attenuated in older people and diabetic patients.
 
Interestingly it was found that long-term exercise could increase the level of these miRNAs in the blood offering better protection against the SARS-CoV-2 virus.
 
To date, clinical data all over the world have showed that elderly individuals and patients with comorbidities have higher risks of developing severe complications and higher mortality rate from COVID-19. However, there is a lack of scientific explanation for this phenomenon. Understanding the potential mechanism underlying the increased susceptibility of elder people and patients with comorbidities to COVID-19 infection is critical for investigating the pathogenesis and estimating the expected global disease burden.
 
Ultilizing high-throughput sequencing and bioinformatics analysis, the  study team identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) that are markedly decreased in the elderly and diabetic groups. They further demonstrated that these miRNAs, either in exosomes or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication.
 
The study found that serum exosomes from young people can effectively inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients.
 
Importantly, 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
The study findings show for the first time that our own endogenous miRNAs could directly inhibit SARS-CoV-2 virus.
 
However this is not surprising since the group’s previous studies have already showed that approximately 89% viruses that infect humans could be targeted by human miRNAs. https://link.springer.com/content/pdf/10.1186/s41544-019-0018-9.pdf
 
The study findings provides strong and direct evidence supporting the theory that miRNAs, particularly extracellular miRNAs, could function as “RNA defense” and protect cells against foreign nucleic acids.
 
Classic immunology tells us that the mammalian immune system is protein-based and immune protection is provided by antibodies, cytokines, interferons and so on.
 
The study findings indicate that miRNAs are an important component of the endogenous RNA-based immune system to fight virus infection, as exemplified here by SARS-CoV-2. This new understanding of miRNA function may provide new perspectives for prevention, surveillance and treatment of COVID-19.
 
The findings also provides an interesting observation that continuous physical exercise could boost miRNA immunity against SARS-CoV-2, which explains why it is important to exercise more during the COVID-19 pandemic but in a safe manner.
 
There are various studies that show that certain phytochemicals also help modulate and also helps to increase expression of relevant miRNA associated with antiviral or anti-inflammatory properties. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631275/
 
https://pubs.rsc.org/en/content/articlelanding/2017/fo/c7fo00739f
 
Furthermore even external plant MiRNAs could also be beneficial in the modulating or increasing expression fo the needed miRNAs.
https://www.nature.com/articles/srep32773
 
https://www.frontiersin.org/articles/10.3389/fgene.2020.552490/full


An epidemiologic study suggested that elder people and patients with comorbidities, such as diabetes, are more susceptible to COVID-19 infection and the development of more severe disease,2–4 a feature shared with the 2003 SARS epidemic.5 Chinese researchers first reported a higher prevalence of diabetes among patients with severe compared to non-severe illness.6

In the initial studies, diabetes patients showed to be 2.26 times more common in patients with more severe COVID-19 compared to those with less severe infection, while at the same time the presence of diabetes entailed an odds ratio of 2.85 of intra-hospital mortality.7

COVID-19 patients with diabetes are admitted more often to intensive care units (ICUs) compared to those without diabetes,8 and the risk of developing severe COVID-19 is higher in people with diabetes.9 The worse the glycemic control, the worse the severity of infection and the greater the risk of mortality.9

Therefore, understanding the potential mechanism underlying the increased susceptibility of elder people and patients with comorbidities to COVID-19 infection is critical for investigating the pathogenesis and estimating the expected global disease burden.

The immune system protects the body from constant attacks by viruses, bacteria and other pathogens. Much of the protection is provided by immune cells. However, immune functions are not restricted to these “specialists”.10 Several lines of evidence indicate that RNA interference (RNAi) plays a role in the antiviral immunity of invertebrates, such as C. elegans and D. melanogaster.11,12

MicroRNAs (miRNAs), a class of non-coding RNAs that are around 22 nucleotides in length, are part of the RNAi system and might also function as an antiviral mechanism in mammals.13

miRNAs have been found to interact with viral genes in several ways. For example, miR-32 restricts the accumulation of the retrovirus primate foamy virus type 1 (PFV-1) in human cells.14 It has also been reported that mice deficient in Dicer-1 (and therefore deficient in mature miRNAs) are more susceptible to vesicular stomatitis virus (VSV) infection.15 Liu et al. calculated the potential miRNA targets in 17 metazoan and viral genomes and proposed that the initial function of miRNAs was predominantly antiviral,16 as evolution proceeded, miRNAs acted more specifically on self-genomes, suggesting that the origin of microRNAs is a defensive rather than a regulatory strategy.

Previous studies by our group and others have shown that extracellular miRNAs are highly stable and can not only serve as biomarkers for various diseases but also be secreted into the extracellular space within exosomes.17–19 Evidences also exist that these exosomes can be taken up by neighbouring or distant cell and subsequently modulate the function of recipient cells.18,20,21

Herein, we tested the hypothesis that circulating miRNAs in exosomes may act as a natural antiviral mechanism to suppress SARS-CoV-2 replication. We provide evidence that several circulating exosomal miRNAs, which were decreased in elder and diabetic people, could inhibit SARS-CoV-2 replication by directly targeting the S protein. Long-term exercise could increase the expression of these exosomal miRNAs and enhance the inhibitory effect on SARS-CoV-2 replication.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355568/

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