miRNAs; a novel strategy for the treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is the seventh member of the bat severe acute respiratory syndrome family. COVID-19 can fuse their envelopes with the host cell membranes and deliver their genetic material. COVID-19 attacks the respiratory system and stimulates the host inflammatory responses, enhances the recruitment of immune cells, and promotes angiotensin-converting enzyme 2 activities. Patients with confirmed COVID-19 may have experienced fever, dry cough, headache, dyspnea, acute kidney injury, acute respiratory distress syndrome, and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. However, these approaches may not be good treatment options. Therefore, the search for an alternative-novel therapy is urgently important to prevent the disease progression. Recently, microRNAs (miRNAs) have emerged as a promising strategy for COVID-19. The design of oligonucleotide against the genetic material of COVID-19 might suppress virus RNA translation. Several previous studies have shown that host miRNAs play an antiviral role and improve the treatment of patients with COVID-19. miRNAs by binding to the 3'-untranslated region (UTR) or 5'-UTR of viral RNA play an important role in COVID-19-host interplay and viral replication. miRNAs interact with multiple pathways and reduce inflammatory biomarkers, thrombi formation, and tissue damage to accelerate the patient outcome. The information in this review provides a summary of the current clinical application of miRNAs for the treatments of patients with COVID-19.

angiotensin‐converting enzyme 2

acute cardiac injury

ADAM metallopeptidase domain 17

acute kidney injury

antagonist miR

acute respiratory distress syndrome

complete complementary miRNA

coronavirus disease 2019

colony‐stimulating factor 1

extracellular vesicles

exportin‐5

gene ontology

interleukin‐1

long noncoding RNAs

microRNAs

messenger RNAs

precursor miRNA

primary miRNAs

RNA‐induced silencing complex

severe acute respiratory syndrome

Toll‐Like receptors

Type II transmembrane serine proteases.

tumor necrosis factor

transactivating response RNA‐binding protein

INTRODUCTION

Coronavirus disease 2019 (COVID‐19) for the first time emerged in Wuhan (the capital of central China's Hubei province) and later spread worldwide (Bernheim et al., 2020; Diao et al., 2020; Lauer et al., 2019). COVID‐19 has been reported as the seventh member of the bat severe acute respiratory syndrome (SARS) family, which is known as SARS‐CoV‐2 (Lauer et al., 2019; Wang et al., 2020; Zhu et al., 2020). Coronaviruses are enveloped positive‐sense RNA viruses that generally cause mild to acute respiratory infection in various species from bats to humans (Chang et al., 2020; Chen, 2020; Fung et al., 2020; Song, 2020). COVID‐19 contains four structural proteins, including nucleocapsid (N) protein and membrane (M), spike (S), and small envelope (E) glycoproteins (Abu‐Izneid et al., 2020). These viruses directly fuse to the plasma membrane, deliver their genetic materials, and complete their life cycle (Cascella et al., 2020; Jan & Arif, 2020). Initial symptoms for most patients with COVID‐19 include fever, headache, shortness of breath, muscle soreness, sputum production, dyspnea, diarrhea, nausea, and fatigue (Bernheim et al., 2020; Huang et al., 2020; Jiang et al., 2020; Kui et al., 2020). A slight decrease in platelet levels and a massive release of tumor necrosis factor (TNF), plasminogen activators, and interleukin‐1 and 6 (IL‐1 and IL‐6) have been reported to stimulate acute endothelial cell activation and microthrombus in lung vascularity (Schultz et al., 2021). COVID‐19 infects the respiratory system, triggers widespread inflammation, promotes the recruitment of immune cells, and angiotensin‐converting enzyme 2 (ACE2) activities (Abdi, 2020; Lauer et al., 2019). In a subset of high‐risk patients (patients with diabetes or preexisting cardiovascular diseases or hypertension), acute cardiac injury, acute kidney injury, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction might be triggered (Chen et al., 2020; Huang et al., 2020; Xu et al., 2020).

Till now, various therapeutic modalities such as antibiotic therapy, antiviral therapy, glucocorticoids therapy, invasive and noninvasive ventilation, and renal replacement therapy have been assessed in clinical settings for COVID‐19 patients (Chen et al., 2020; Chen et al., 2020; Heymann & Shindo, 2020; Huang et al., 2020; MacLaren et al., 2020; Wang et al., 2020; Zhou et al., 2020). However, these strategies are not likely to be safe and effective treatment options against COVID‐19 (Jean et al., 2020; Momekov & Momekova, 2020). Therefore, the search for an alternative‐novel therapy is urgently important to prevent the disease progression (Widiasta et al., 2020). Recently, microRNAs (miRNAs) have been emerged as antiviral regulators of viral genes (Gong & Zhang, 2020; Huang et al., 2021; Ramaiah, 2020). miRNAs through silencing genes play an important role in controlling the expression of transcription factors (Waheed & Zeng, 2020). Hence, it may be feasible to use miRNAs to overcome COVID‐19 (El‐Nabi et al., 2020; Mishra et al., 2020). miRNA‐based therapeutic is a promising approach against heart failure or cardiovascular diseases, neurological disorders, tumorigenesis, and viral infection (Condrat et al., 2020; Cui et al., 2021; Takahashi et al., 2019). The design of oligonucleotide against the genetic material of COVID‐19 might suppress virus RNA translation (Hassab Elnabi, 2020; Yu et al., 2020). Recent evidence suggests that miRNAs can improve the treatment of patients with COVID‐19 (El‐Nabi et al., 2020; Garg et al., 2021; Hassab Elnabi, 2020; Schultz et al., 2021). The information in this review provides a summary of the current clinical application of miRNAs for the treatments of patients with COVID‐19.

THE CANONICAL miRNA BIOGENESIS

miRNAs are a family of noncoding RNAs with an average of 22 nucleotides that interact with messenger RNAs (mRNAs) and play critical roles in controlling gene expression in a variety of biological processes (DeVeale et al., 2021). In most cases, miRNAs by miRNA‐binding sites in the 3′‐untranslated region (UTR) of the target mRNAs stimulate mRNA degradation and regulate posttranscriptional expression (Valinezhad Orang et al., 2014). Besides, miRNAs can bind with the 5′‐UTR, gene promoters, and coding sequence (O'Brien et al., 2018).

RNA polymerase II or III transcribed miRNA genes and generates pri‐miRNAs (primary miRNAs) (Borchert et al., 2006; Gregory et al., 2005). Subsequently, Drosha/DGCR8 holoenzyme (microprocessor cleavage) mediates processing of the pri‐miRNA to generate the precursor miRNA (pre‐miRNA) or a hairpin structured precursor (∼60 to 70 nt) in the nucleus (Zeng et al., 2017). The pre‐miRNAs by Exportin‐5 (Exp5) and Ran‐GTP (a nucleocytoplasmic transporter) are delivered to the cytoplasm (Wu et al., 2018). The pre‐miRNAs hairpin cleaved into a ∼22 nucleotide duplex through Dicer (RNase III endonuclease) with the transactivating response RNA‐binding protein to form a mature miRNA duplex (Fareh et al., 2016; Graves & Zeng, 2012; Ha & Kim, 2014). The mature miRNAs are created via RNA‐induced silencing complex (RISC) (Berezikov et al., 2007; Du & Zamore, 2005; Ruby et al., 2007). miRNA binds with the AGO protein (RISC) to target mRNA and trigger mRNA cleavage, mRNA degradation, and translation repression (Lam et al., 2015; Pu et al., 2019) (Figure 1). It is now accepted that the epigenetic modulation of miRNA expression plays an important role in several pathological processes after viral infections.

Figure 1

miRNA at cellular level due to COVID‐19 infection. RNA polymerase II or III transcribed miRNA genes and generates pri‐miRNAs (primary miRNAs). Subsequently, Drosha/DGCR8 holoenzyme (microprocessor cleavage) mediates processing of the pri‐miRNA to generate the precursor miRNA (pre‐miRNA) or a hairpin structured precursor (∼60‐ to 70 nt) in the nucleus. The pre‐miRNAs by Exportin‐5 (Exp5) and Ran‐GTP (a nucleocytoplasmic transporter) are delivered to the cytoplasm. The pre‐miRNAs hairpin cleaved into a ∼22 nucleotide duplex through Dicer (RNase III endonuclease) with the transactivating response RNA‐binding protein (TRBP) to form a mature microRNA duplex. The mature miRNAs are created via RNA‐induced silencing complex. miRNA binds with the AGO protein (RNA‐induced silencing complex [RISC]) to target messenger RNA (mRNA) and trigger mRNA cleavage, mRNA degradation, and translation repression. COVID‐19 contains four structural proteins, including nucleocapsid (N) protein and membrane (M), spike (S), and small envelope (E) glycoproteins. miRNAs by binding to the coding region or 5′‐UTR of viral RNA play an important role in COVID‐19‐host interplay and viral replication. COVID‐19, coronavirus disease 2019; miRNA, microRNA; UTR, untranslated region

THE POTENTIAL FUNCTION OF miRNAs FOLLOWING COVID‐19 INFECTION

Growing evidence shows that the host‐encoded miRNAs could modulate virus replication and pathogenesis (Khan et al., 2020; Tribolet et al., 2020; Wong et al., 2020; Zhang et al., 2020; Zheng et al., 2020). miRNAs through binding with viral RNA interact with different species or strain of viruses (Križnik et al., 2020; Trobaugh & Klimstra, 2017). miRNAs by binding to the 3′‐UTR (El‐Nabi et al., 2020; Liu et al., 2017) or 5′‐UTR of viral RNA play an important role in COVID‐19‐host interplay and viral replication (Demirci & Adan, 2020; Nersisyan et al., 2020). miRNAs inhibited tissue damage and coagulation disturbs by suppressing coagulation cascade, cell death genes, and inflammatory agents in severe COVID‐19 patients (Schultz et al., 2021).

Table 1 shows the most important miRNAs from the scientific literature that might act as good targets for COVID‐19 drug development.

Table 1

The most important miRNAs that might act as good targets for COVID‐19 drug development

miRNAs	Target	Result	Ref.
miR‐125a‐3p	TNF, CXCL10, IL2, IL7, IL10, IL15, and Factor XIII	Reduces the systemic inflammation, coagulation disturbs, and cell death	(Schultz et al., 2021)
miR‐125b‐1‐3p	TNF, IFN, CCL3, CXCL10, IL10, IL17A, IL18, IL33, Factor III, IX, XIII, and GSDME
miR‐769‐3p	TNF and IFN	Decrease the cell death and tissue damage
miR‐202‐3p
let‐7e‐5p	IL1A, IL1B, IL6R, IL10, IL15, TNF, RIPK1, CASP8, Factor VIII, and CSF3	Reduces the coagulation activation and cell death
miR‐21	Myocardial/cardiomyocyte cells	Enhance endothelial cell dysfunction, inflammation, and myocardial damage	(Garg et al., 2021)
miR‐155
miR‐208a
miR‐499
miR‐126	Endothelial cells	Protecting from endothelial damage
has‐miR‐17‐5p		Antiviral effect during host infection	(Khan et al., 2020)
has‐miR‐20b‐5p
hsa‐miR323a‐5p
miR‐18	ACE2	Kidney problems	(Widiasta et al., 2020)
miR‐1207‐5p	CSF1	Enhances macrophage recruitment and the acute inflammatory response	(Bertolazzi et al., 2020)
hsa‐miR‐588, hsa‐miR‐587, and hsa‐miR‐582‐5p	ACE2	Enhance lung pathogenesis and injury	(Kim et al., 2020)
hsa‐miR‐221‐3p and hsa‐miR‐95‐5p	ADAM17
hsa‐miR‐140‐3p and hsa‐miR‐1255b	TMPRSS2
miR‐5197–3p, miR‐4778‐3p, and miR‐6864‐5p	The KEGG and GO pathways	Increases the pathogenicity	(Arisan et al., 2020)
miR‐8066	The KEGG pathway, TGF‐beta signaling, PRLR, CXCL6, IL6, IL17, and ACVR1 genes
miR‐5197‐3p	Enhances the interaction of cc‐miR2 with the gRNA	Decreases the pathogenicity	(Ivashchenko et al., 2020)
hsa‐let‐7a‐g/i	TMPRSS2	Regulation of viral receptor and the host immunity	(Pontecorvi et al., 2020)
hsa‐miR‐98‐5p	TMPRSS2
hsa‐miR‐145	ADAM17
hsa‐miR‐222	ADAM17
hsa‐miR‐19a/b‐3p	Furin
hsa‐miR‐20b	Furin
hsa‐miR‐106a	Furin
hsa‐miR‐4661‐3p	3′‐UTR of the S gene	Inhibits the viral gene expression	(Liu et al., 2020)
MR147‐3p	TMPRSS2	Enhances the gastrointestinal infection

Abbreviations: ACE2, angiotensin‐converting enzyme 2; ADAM17, ADAM metallopeptidase domain 17; cc‐miR2, cc‐miR for COVID‐19; CSF1, colony‐stimulating factor 1; GO, gene ontology; gRNA, mRNA of the COVID‐19 genome; miRNA, microRNAs; TGF, transforming growth factor; TMPRSS2, Type II transmembrane serine proteases.

Schultz et al. (2021) revealed that the MSCs‐derived extracellular vesicles could carry small and long noncoding RNAs and regulate the behavior of target cells. Their results showed that various miRNAs were associated with exacerbated cytokines and chemokines (258 miRNAs), cell death genes (266 miRNAs), and coagulation cascades (148 miRNAs) (Schultz et al., 2021). Based on their analysis, miR‐125a‐3p binds to the 3′‐UTR region of TNF, CXCL10, IL2, IL7, IL10, IL15, and Factor XIII gene. miR‐125a‐3p reduces the systemic inflammation, coagulation disturbs, and cell death in severe COVID‐19 patients. miR‐125b‐1‐3p is another isoform that targets the 3′‐UTR region of the TNF, interferon (IFN), CCL3, CXCL10, IL10, IL17A, IL18, IL33, Factor III, IX, XIII, and GSDME genes. miR‐769‐3p and miR‐202‐3p by targeting the 3′‐UTR region of the TNF and IFN genes can decrease the cell death and tissue damage. In severe COVID‐19 ICU patients, let‐7e‐5p by targeting the 3′‐UTR region of the IL1A, IL1B, IL6R, IL10, IL15, TNF, RIPK1, CASP8, Factor VIII, and CSF3 genes could reduce the coagulation activation and cell death (Schultz et al., 2021).

Garg et al. (2021) evaluated changes in five circulating cardiovascular miRNAs, including miR‐21 (fibrosis‐associated miRNA), miR‐126 (endothelial miRNA), miR‐155 (cardiovascular disease and inflammation‐associated miRNA), miR‐208a (myocyte‐associated miRNA), and miR‐499 (myocyte‐associated miRNA) in patients with mechanically‐ventilated COVID‐19. They found that serum concentration of four miRNAs such as miR‐21, miR‐155, miR‐208a, and miR‐499 were significantly increased in COVID‐19 patients. Whereas serum concentration of miR‐126 (protective from endothelial damage) was significantly reduced compared to healthy controls. According to previous studies, miR‐21 and miR‐126 participate in endothelial cell dysfunction, miR‐155 stimulates inflammation, and miR‐208a and miR‐499 are associated with myocardial/cardiomyocyte damage (Garg et al., 2021; Hartmann et al., 2016). Hence, the upregulation of these miRNAs might be a predictor of inflammation and myocardial damage (Garg et al., 2021).

Khan et al. (2020) showed that three host miRNAs, including has‐miR‐17‐5p, has‐miR‐20b‐5p, and hsa‐miR‐323a‐5p had an antiviral effect against COVID‐19. They suggested that miRNAs may specifically inhibit several Toll‐Like receptors pathways to modulate the host antiviral defense mechanism. Guterres et al. (2020) followed different stages of COVID‐19 infection and found some miRNAs for positive‐sense viral RNA (34 miRNA) and negative‐sense (45 miRNAs) that target the key COVID‐19 genes. Bertolazzi et al. (2020), reported that COVID‐19 as an exogenous competing RNA could upregulate the expression of miR‐1207‐5p. In severe COVID‐19, miR‐1207‐5p by targeting the CSF1 gene (colony‐stimulating factor 1 or macrophage colony‐stimulating factor) enhanced macrophage recruitment and the acute inflammatory response. Although decrease in ACE2 as a transmembrane protein is critical in ARDS pathogenesis (Imai et al., 2005), previous studies demonstrated that ACE2 is responsible for various indications of COVID‐19 and kidney problems (Hardenberg & Luft, 2020; Perico et al., 2020). Widiasta et al. (2020) illustrated that miR‐18 (miRNA in nephropathy) can regulate ACE2 expression following COVID‐19 infection. Therefore, miR‐18 may be a suitable target for the kidney pathogenesis of COVID‐19 and ACE2 related diseases. Nersisyan et al. (2020) evaluated the interaction of six miRNAs, including miR‐21‐3p, miR‐195‐5p, miR‐16‐5p, miR‐3065‐5p, miR‐424‐5p, and miR‐421 with human COVID‐19 RNAs. They suggested that the expression of miR‐21‐3p was significantly increased in mouse lungs fallowing infection. Hosseini Rad and McLellan (2020) observed that the expression of miR‐197‐5p was upregulated in patients with cardiovascular disease. Therefore, these patients were more susceptible to COVID‐19 infection. Arisan et al. (2020) illustrated that seven miRNAs, including miR‐8066, miR‐5197, miR‐3611, miR‐3934‐3p, miR‐1307‐3p, miR‐3691‐3p, and miR‐1468‐5p by targeting the KEGG pathways increased viral pathogenicity and host responses. They found that miR‐5197‐3p, miR‐4778‐3p, and miR‐6864‐5p influenced on the gene ontology and KEGG pathways, and significantly promoted COVID‐19 pathogenesis. They also reported that miR‐8066 by targeting the KEGG pathway, TGF‐beta signaling, PRLR, CXCL6, IL6, IL17, and ACVR1 genes increased the pathogenicity of COVID‐19. So, these pathways may help to assess better therapeutic in COVID‐19‐infected patients.

Ivashchenko et al. (2020) found that synthetic miRNAs such as complete complementary miRNA (cc‐miR as therapeutic agents can be used to inhibit the reproduction of the virus. They revealed that out of 2565 miRNAs, miR‐4778‐3p, miR‐6864‐5p and miR‐5197‐3p were the most effectively interacting with the gRNA of SARS‐CoV, MERS‐CoV, and COVID‐19, respectively. miR‐5197‐3p enhanced the interaction of cc‐miR2 (cc‐miR for COVID‐19, 25 nt) with the mRNA of the COVID‐19 genome, without side effects on the host genome or competition with other sides.

Fulzele et al. (2020) assumed that some of the human miRNAs downregulated with aging which might affect COVID‐19‐host cell interaction and enhance severity and mortality among adult individuals more than 65 years with COVID‐19. Kim et al. (2020) examined on hamster lung tissues infected by COVID‐19 and showed that five miRNAs, including hsa‐miR‐15a‐5p, hsa‐miR‐15b‐5p, hsa‐miR‐195‐5p, hsa‐miR‐16‐5p, and hsa‐miR‐196a‐1‐3p could bind to COVID‐19. Besides, seven miRNAs were found to bind to the ACE2 (hsa‐miR‐588, hsa‐miR‐587, and hsa‐miR‐582‐5p), ADAM17 (ADAM metallopeptidase domain 17) (hsa‐miR‐221‐3p and hsa‐miR‐95‐5p), and type II transmembrane serine proteases (TMPRSS2) (hsa‐miR‐140‐3p and hsa‐miR‐1255b) receptor proteins. They also found that levels of expression of five miRNAs, including hsa‐miR‐15b‐5p, hsa‐miR‐195‐5p, hsa‐miR‐221‐3p, hsa‐miR‐140‐3p, and hsa‐miR‐422a altered after infection. They suggested that hsa‐miR‐15b‐5p and hsa‐miR‐195‐5p may be suitable therapeutic biomarkers for COVID‐19.

Mukhopadhyay et al. (2020) determined novel hypothalamic miRNAs that targeting to the ACE2 (31 miRNAs) and TMPRSS2 (29 miRNAs) genes. Therefore, these miRNAs via regulation of ACE2 and TMPRSS2 expression can be used to treat neurological symptoms in COVID‐19 patients.

Li et al. (2020) evaluated the expression of miRNAs in the peripheral blood from patient with COVID‐19. They found that the expression of some miRNAs was increased (35 miRNAs) or decreased (38 miRNAs). Besides, the expression of three miRNAs, including miR‐183‐5p, miR‐627‐5p, and miR‐144‐3p was significantly decreased. Pontecorvi et al. (2020) reported that the sex hormones in human host cells play important roles in COVID‐19 lethality. They presented seven gender‐associated miRNAs, including hsa‐let‐7a‐g/i, hsa‐miR‐98‐5p, hsa‐miR‐145, hsa‐miR‐222, hsa‐miR‐19a/b‐3p, hsa‐miR‐20b, and hsa‐miR‐106a, which were localized on the X‐chromosome and participated in regulation of COVID‐19 receptors and host immunity. These miRNAs were reported to target the TMPRSS2, ADAM17, and Furin genes. Several hormones such as Estrogen/Erα, progesterone, androgen, Vitamin D, and 17β‐Estradiol have been already identified that control the expression of these miRNAs.

Liu et al. predicted that hsa‐miR‐4661‐3p could bind at the potential 3′‐UTR of the S gene of COVID‐19 and repressed the viral gene expression. In addition, MR147‐3p as a virus‐encoded miRNA increased the expression of TMPRSS2 and the gastrointestinal infection of COVID‐19 (Liu et al., 2020). Therefore, miRNA can be a potent diagnostic biomarker for COVID‐19 (Chauhan et al., 2020; Greco et al., 2020).

LIMITATIONS OF miRNAs AGAINST COVID‐19

miRNAs are an attractive therapeutic target that would facilitate the diagnosis and treatment of COVID‐19 infection (Abu‐Izneid et al., 2020; Canatan et al., 2020; Pierce et al., 2020). miRNAs as potent epigenetic regulators stimulate the innate and adaptive immune system and influence the viral propagation (Mukhopadhyay & Mussa, 2020). However, different sets of miRNAs are expressed in the host system which target an entire immune pathway (Cho et al., 2020; Jia & Wei, 2020). Also, various miRNAs with multi‐step maturation need several strategies to enhance miRNAs function and develop miRNAs‐based therapeutics against COVID‐19 (Abu‐Izneid et al., 2020). Besides, manipulating endogenous miRNA to reduce the risk of COVID‐19 infection may cause negative effects on the host genome (Ivashchenko et al., 2020; Mishra et al., 2020). Recently, the viral‐encoded miRNAs have been shown to target several signaling pathways and critical cellular processes such as transcription, metabolism, and defense (Demirci & Adan, 2020; Mishra et al., 2020).

Demirci and Adan (2020) provided a list of miRNAs which involved in host‐COVID‐19 interaction. They assumed that the gonadotropin‐releasing hormone receptor, Wnt, EGF, FGF, CCKR, and PDGF signaling pathways might be influenced by viral miRNA. Yu et al. (2020) used miRNA precursor prediction tools and identified location of three novel coronavirus miRNA precursors, including miR‐P1‐3p (first, second, and third). The COVID‐19‐encoded miRNAs as autocrine or paracrine agonists of host cells increased nuclear factor kappa B activity and stimulated proinflammatory cytokines (Arisan et al., 2020). Therefore, further investigation is required to identify specific miRNAs that target and stop virus‐induced infection (Farshbaf et al., 2020; Pontecorvi et al., 2020).

FUTURE STRATEGY USING miRNAs AGAINST COVID‐19

Several previous studies identified the interactions between miRNA and SARS‐CoV‐2 and reported novel approaches against SARS‐CoV‐2 infection (Rizkita & Astuti, 2021). It has also been reported that antiviral miRNAs (miR‐24, miR‐124, and miR‐744) by targeting the p38 MAPK pathway play an important role against respiratory virus infection (McCaskill et al., 2017). Although current strategies using miRNAs for treating COVID‐19 are limited, potential binding sites on COVID‐19 may highlight the roles of miRNAs in regulating COVID‐19 infections (Alam & Lipovich, 2021; Hum et al., 2021). miRNAs have been shown to interact with the viral genome, affect vital processes, regulate the host's cellular microenvironment and the innate immune network (Demongeot & Seligmann, 2020; Hum et al., 2021). Recently, two approaches for miRNA‐targeted therapy by the use of miRNA antagonists or inhibitors (Cobomarsen, an inhibitor of miR‐155) (Seto et al., 2018) and miRNA mimics (Remlarsen, a miR‐29 mimic) (Gallant‐Behm et al., 2019) were found to support the efficient expression of proteins in the host and decrease the negative effects of miRNAs on the host cells (Gasparello et al., 2021). Miravirsen is a miR‐122 antagonist and the first miRNA‐based drug, which downregulates viral RNA levels (Santaris Pharma A/S, Phase II clinical trial) (Janssen et al., 2013; Okuyan & Begen, 2021). Therefore, antagonist miR (antimiR) and miR mimic could be innovative approach for the treatment of COVID‐19 infections (Rizkita & Astuti, 2021). However, miRNA‐COVID‐19 interaction is a complex process that may enhance or suppress viral replication (El‐Nabi et al., 2020; Fani et al., 2021).

Among the current efforts for the treatment of COVID‐19, recent experiments developed animal models for COVID‐19 to accelerate the preclinical testing of vaccines (Muñoz‐Fontela et al., 2020). Corbett et al. (2020) assessed the mRNA‐1273 vaccine against COVID‐19 and showed rapid protection in the upper and lower airways in nonhuman primates. Despite the challenges of safe and effective vaccine manufacturing (Forman et al., 2021; Heaton, 2020), in the case of miRNA‐COVID‐19 interaction, further experimental is still required to generate miRNA‐based animal models of COVID‐19 to improve vaccine efficacy.

CONCLUSION

COVID‐19 infection stimulates inflammation and endothelial cell damage in multiorgans with cardiac injury (Garg et al., 2021). Viruses‐derived miRNA can impact the host miRNA expression level and improve virus pathogenicity (Abu‐Izneid et al., 2020). Host‐derived miRNAs play essential roles in limiting viral replication (Barbu et al., 2020; Wong et al., 2020). There is evidence that miRNAs are able to downregulate the viral replication, modulate viral infectious progress, and enhance the survival rates in severe COVID‐19 patients (Schultz et al., 2021). miRNAs interact with multiple pathways and reduce inflammatory biomarkers, thrombi formation, and tissue damage to accelerate the patient outcome (Schultz et al., 2021).

According to the literature, the interaction of host miRNA with the COVID‐19‐encoded mRNAs may alter by age, underlying chronic disease (diabetes, lung, and cardiovascular disorders), and gender. Also, the ACE2, TMPRSS2, and ADAM17 genes might serve as potent targets in patients with COVID‐19. However, more investigations are needed to confirm their interactions with miRNAs in COVID‐19 and in other infectious events.

CONFLICT OF INTERESTS

None of the authors have any conflict of interest.

AUTHOR CONTRIBUTIONS

Hao Ying, Mohsen Ebrahimi, and Maryam Farzaneh have been involved in drafting the manuscript. Mona Keivan, and Seyed Esmaeil Khoshnam have made substantial contributions to the revising of the manuscript and the design of the Table. Sarvenaz Salahi has made a substantial contribution to the writing and the design of the Figure. All authors read and approved the final manuscript.