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. A recently published mini-review in the Frontiers in Microbiology on the altered expression of small non-coding RNAs during coronavirus-mediated infections.
Authors Pallabi Bhattacharyya and Subhas C. Biswas, from CSIR-Indian Institute of Chemical Biology, India, share how this insight may provide a better understanding of severe acute respiratory syndrome pathogenesis coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19).
Several promising antiviral strategies are underway, specifically for containing the current pandemic, COVID-19. Since its discovery in Wuhan, China, in December 2019, the SARS-CoV-2 has spread worldwide. The virus has infected over 43.4 million people and claimed over 1.15 million lives worldwide.
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.
SARS-CoV-2 is a beta-CoV possessing a positive-sense single-stranded RNA genome. It is one of the CoV known to infect humans.
ncRNAs are instrumental in regulating the host-virus dynamics
It is observed that during RNA virus-mediated infections, particularly in the case of human coronavirus (HCoV)-mediated diseases, many small ncRNAs play an important role.
It is known that RNA viruses, including CoVs, can encode microRNAs(miRNA)-like small regulatory RNAs. These are differentially expressed in the host cells when infected by each of the viruses.
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.
miRNA-based gene regulation during HCoV infection, including SARS-CoV-2
Studies show 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.
In this review, the authors have presented some significant findings:
1. 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.
2. 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.
3. 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.
4. 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.
RNA interference (RNAi)-based antiviral therapies targeted at miRNA-mediated gene regulation show clinical potential
The locked nucleic acids or LNAs, and similar such RNAi-based antiviral therapies offers 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 authors discuss the delivery strategies for successful RNAi-based therapeutics against COVID-19, that may be aerosolized and easily administered intranasally.
Significance of RNAi as a therapeutic strategy to treat SARS-CoV-2–mediated infection
Using miRNAs is advantageous because it has functional flexibility - 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.
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.
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.
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.