COVID-19 Genetics-Genomics: Role of miRNAs and RNA Interference (RNAi) In SARS-CoV-2 Infection And Pathogenesis

COVID-19 Genetics-Genomics: Indian researchers from CSIR-Indian Institute of Chemical Biology-India in a new study have revealed the critical roles that non-coding RNAs (ncRNAs) and RNA Interference (RNAi) play in SARS-CoV-2 infection and pathogenesis.


 
Despite the fact clinical trials of a number of promising antiviral drugs and vaccines against COVID-19 are underway, it is hard to predict how successful these drug- or vaccine-based therapeutics are eventually going to be in combating COVID-19 because most of such therapeutic strategies have failed against human coronaviruses such as SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus) responsible for similar pandemics in the past. In that context, the study brings scientific attention to another group of endogenous regulatory molecules, the small non-coding RNAs, especially the microRNAs, which are found to regulate critical cellular pathways in a number of disease conditions, including RNA viral infections. This study will focus on understanding the effect of altered microRNA expression during coronavirus-mediated infections and how it may provide clues for further exploring the pathogenesis of SARS-CoV-2, with a view of developing RNAi-based therapeutics and biomarkers against COVID-19.
 
The study findings are published in the journal: Frontiers In Microbiology https://www.frontiersin.org/articles/10.3389/fmicb.2020.571553/full
 
The ncRNAs or Non-coding RNAs are ribonucleic acid (RNA) molecules that are not translated into proteins. Small non-coding RNAs (ncRNAs)-mediated gene regulation in RNA virus infections is an emerging area for understanding the pathogenesis and therapeutic prospects.
 
The study team presents a mini-review on the altered expression of small non-coding RNAs during coronavirus-mediated infections.
 
Researchers Dr Pallabi Bhattacharyya and Dr Subhas C. Biswas, from CSIR-Indian Institute of Chemical Biology, India, share how this insight may provide a better understanding of SARS-CoV-2, the causal agent of COVID-19.
 
To date scientists from diverse disciplines are exploring new and novel avenues to find successful treatment to combat this COVID-19 infection. In this context, the authors bring to scientific attention the use of small non-coding RNAs in effectively controlling the disease. These molecules are found to regulate critical cellular pathways in several disease conditions, including RNA viral infections.
 
The SARS-CoV-2 is a beta-coronavirus possessing a positive-sense single-stranded RNA genome. It is one of the coronaviruses known to infect humans.
 
It has been found that during RNA virus-mediated infections, particularly in the case of human coronavirus (HCoV)-mediated diseases, many small ncRNAs play an important role.
 
Also it has already been known that RNA viruses, including coronaviruses can encode microRNAs (miRNA)-like small regulatory RNAs. These are differentially expressed in the host cells when infected by each of the viruses.
 
Importantly a class of small viral RNAs (svRNAs) is also known to modulate the host-response by regulating the production of specific pro-inflammatory cytokines, specifically the deadly antiviral  ;cytokine storm - an uncontrolled systemic inflammatory response. However, the biogenesis and mechanism of function of these ncRNAs are not very clear.
 
Past research has shown that the host miRNAs may regulate viral replication and proviral host factors. The miRNAs affect pathogenesis in many respiratory RNA viral infections. This understanding is, however, preliminary and upcoming in the case of CoV-mediated diseases.
 
The study authors have presented some significant findings:
 
- HCoV nucleocapsid protein (N) can directly bind to small regulatory RNAs (host miRNAs and siRNAs) and modulate (read suppress) antiviral immune response in the host. (The authors highlight this as an important focus area for designing therapeutic antiviral strategies if any such N protein-miRNA–mediated interaction is also elicited in the form of host response mechanism during SARS-CoV-2 infection.)
 
-Endonuclease APE1 (apurinic/apyrimidinic endonuclease 1) can cleave miRNAs and other RNA components of SARS-CoV (This RNA-cleaving property of APE1 may be a tool to target specific regulatory RNAs implicated in viral infections, including that of SARS-CoV-2.)
 
-SARS-CoV exploits the miRNA machinery of bronchoalveolar stem cells (BASCs) for persistent infection (A few upregulated miRNAs triggered the virus to suppress its viral replication and thus escape the host immune response, and a few downregulated miRNAs led to pro-inflammatory cytokines.)
 
-Computational predictions of altered miRNAs (The in silico studies of different miRNAs dysregulation during SARS-CoV-2 infection require experimental validation in vitro and in vivo models.)
 
According to the authors, RNA interference (RNAi)-based antiviral therapies targeted at miRNA-mediated gene regulation show clinical potential.
 
Interestingly the locked nucleic acids or LNAs, and similar such RNAi-based antiviral therapies offer various advantages: they are stable, show high target specificity, and lower off-target effects, they are not known to interfere with other therapeutics, and they may be used in a combinatorial manner for increased efficacy of treatment.
 
The study team discusses the delivery strategies for successful RNAi-based therapeutics against COVID-19, that may be aerosolized and easily administered intranasally.
 
Utilizing miRNAs is advantageous because it has functional flexibility ie miRNAs can evolve relatively fast and target new mRNA (messenger RNA) transcripts. Considering the acute nature of SARS-CoV-2 infections (~ 2-4 weeks) and the rapid evolution of the virus into various mutant subtypes and strains, modulation of antiviral genes within a short period as offered by the miRNA machinery is one of the best options for mitigating the pandemic.
 
Also the altered miRNA expression may be in favor of or against the existence and replication of the virus inside the host, depending on the host-virus dynamics during viral infection. The miRNA-mediated gene regulation is unique because a single miRNA may have multiple mRNA targets, or a single mRNA may be targeted by multiple miRNAs, making it a suitable therapeutic candidate.
 
In order to get the complete picture, the study of regulatory ncRNAs like miRNAs demands serious research attention as it may reveal critical cues for understanding 1) the viral disease pathogenesis, 2) changes in the host immune response mechanisms during viral infections, and 3) any effect on the replication or persistence of the virus inside the host. These may help in developing successful therapeutics against SARS-CoV-2, whose infectivity has encompassed the world population.
 
Importantly the prospect of a therapeutic target in the SARS-CoV-2 virus is given a fresh perspective by assessing the endogenous regulatory molecules if these non-coding molecules may encode any promising tool to mitigate the infection.
 
In the past, no vaccine or drug has been proven effective against HCoVs, including the likes of SARS-CoV or MERS-CoV, which too were responsible for pandemic respiratory diseases in 2002 and 2012, respectively. Although clinical trials of potential vaccines and drug targets are ongoing against COVID-19, it is too early to predict how useful they are eventually going to be in eliminating SARS-CoV-2, which is reported to be mutating and evolving at a considerable rate. In such a scenario, identification of altered or dysregulated miRNAs during SARS-CoV-2 infection may prove instrumental in designing RNAi-based therapeutics for combating COVID-19 and may open up new avenues for developing biomarkers against this deadly pandemic in the future.
 
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