Unraveling the Genetic and Biological Factors Underlying COVID-19 Severity: Insights from miRNA Analysis


The emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed significant challenges to global health. While our scientific understanding of the virus and the disease has progressed rapidly over the past three years, the variation in clinical symptoms observed among infected individuals remains a perplexing question.

From asymptomatic cases to severe and often fatal disease, the factors influencing COVID-19 symptomatology are complex, involving genetic, biological, environmental, and social elements.

This article explores the role of microRNAs (miRNAs) in the context of COVID-19, shedding light on their potential contributions to disease severity and progression.


MicroRNAs (miRNAs) are small RNAs with critical functions in several physiological processes 13. Mature miRNAs are produced from primary transcripts (pri-miRNAs), which are processed by Drosha proteins into precursor miRNAs (pre-miRNAs), each of which consists of 5p and 3p arms and a terminal loop.

The pre-miRNAs are transported to the cytoplasm by exportin 5 and are divided by Dicer to release the terminal loop and 5p/3p duplex. Finally, according to the hydrogen bond theory, the 5p or 3p arm is selectively loaded onto the RNA-induced silencing complex 14-16. However, studies have reported different arm selection preferences of miRNA (for the 5p or 3p arms) in different tissues, developmental stages, and species and during cancer progression 17-25.

Researchers have hypothesized that these arm selection preferences are regulated by target-mediated miRNA protection 26, 27. MiRNA performs its biological functions by targeting the 3′-untranslated region (3′-UTR) of protein-coding genes to degrade mRNA or inhibit protein translation. Therefore, an single pre-miRNA structure can generate two mature miRNAs, miR-#-5p and -3p, which might have distinct functions in distinct cell types or under distinct physiological conditions 28.

miRNAs play key roles in antiviral responses and viral pathogenesis in hosts infected with herpesviruses, polyomaviruses, retroviruses, pestiviruses, and hepatitis viruses as well as coronaviruses 29. The induction of miRNA expression by viral infection boosts the immune response by altering the gene expression profiles of host cells.

The miRNAs induced by these viruses can be used to identify targets involved in the viral life cycle. Therefore, several studies have developed and evaluated the use of virus-induced miRNAs in antiviral therapies, including treatments for human immunodeficiency virus 1, herpes simplex virus, dengue fever, influenza, and hepatitis C 30.

In human cells, miRNAs can also play a role in preventing viral infection by blocking target pathways required for viral penetration, replication, and spread, including the p38 MAPK, PI3K/Akt, FAK, IFN-gamma, TGF-beta, interleukin, IGF1, and TRAIL signaling pathways 7, 35-37. Khan et al. identified three miRNAs (hsa-miR-17-5p, hsa-miR-20b-5p, and hsa-miR-323a-5p) that exhibit antiviral effects against SARS-CoV-2 during host infection 7.

Some miRNAs, including hsa-miR-8066, hsa-miR-5197-3p, and hsa-miR-3934-3p, modulate the SARS-CoV-2 life cycle by influencing biosynthesis 38. Sato et al. reported that hsa-miR-15b-5p interacts with RNA polymerase, which might affect SARS-CoV-2 replication 39. A comprehensive analysis of the cell-free RNA profiles of the plasma of patients with COVID-19 and healthy controls revealed that the expression of hsa-let-7 family members, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-451a, and hsa-miR-316 in patients with COVID-19 was significantly lower than that in healthy individuals. The downregulation of these miRNAs in patients with COVID-19 leads to IL-6/IL-6R hyperactivation by directly targeting the 3’UTR of IL-6/IL-6R, thereby enhancing the cytokine storm induced by SARS-CoV-2 infection 40.

Meidert et al. reported that the differential expression of hsa-miR-3168, hsa-miR-146a-5p, and hsa-let-7e-5p in patients with COVID-19 can affect the expression of inflammation-related genes, including IL-6, IL-8, and Toll-like receptor 4 (TLR4)41. In addition to influencing inflammation-related pathways, host miRNAs may negatively regulate the viral life cycle by inhibiting viral entry or the translation of the viral genome; alternatively, the binding of miRNAs to the 5′ or 3′UTR may lead to greater RNA stability and increased viral replication 42.

Overall, miRNAs participate in SARS-CoV-2 infection and pathogenesis through four mechanisms: (1) host cell miRNA expression interfering with SARS-CoV-2 cell entry; (2) SARS-CoV-2-derived RNA transcripts acting as competitive endogenous RNAs (ceRNAs) that may attenuate host cell miRNA expression; (3) host cell miRNA expression modulating SARS-CoV-2 replication, and (4) SARS-CoV-2-encoded miRNAs protecting SARS-CoV-2 from degradation and silencing the expression of host protein-coding genes (Figure ​(Figure22).

Figure 2 – Four putative mechanisms of miRNA participation in SARS-CoV-2 pathogenesis.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346380/

Factors Influencing COVID-19 Severity

Previous research has identified several factors that contribute to the severity of COVID-19, including age, gender, and underlying health conditions such as diabetes, hypertension, and obesity.

Additionally, various blood markers, such as elevated levels of D-dimers, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), Interleukin 6 (IL-6), IL-10, lactate dehydrogenase (LDH), procalcitonin, and albumin, have been associated with severe disease.

Notably, neutrophils have been found to play a critical role in COVID-19 pathophysiology, with activated circulating neutrophils serving as predictors of clinical illness.

Genetic Variation and miRNAs in COVID-19

Genetic variation has been shown to influence COVID-19 susceptibility, severity, and clinical outcomes. However, limited research has focused on the potential roles of miRNAs, which are small, non-coding RNAs that regulate gene expression. These miRNAs bind to complementary mRNA transcripts, either blocking translation or marking them for degradation.

Dysregulated miRNA expression can indicate aberrant immune function and has been implicated in various diseases, including cancers, inflammatory disorders, and malaria.

Role of miRNAs in COVID-19

Although our understanding of miRNAs’ roles in response to SARS-CoV-2 is still in its early stages, several studies have identified aberrant miRNA expression during COVID-19 progression. These studies have highlighted differentially expressed miRNAs between COVID-19 patients and healthy controls, with correlations found between miRNA levels and proinflammatory cytokines. Dysregulated miRNAs have also been associated with ICU admission and survival outcomes.

Mechanisms of miRNA Regulation and Implications

Studies have investigated the mechanisms underlying miRNA regulation in COVID-19. For instance, functional roles have been identified for specific miRNAs in modulating the expression of ACE2 and DPP4 receptors, which play critical roles in the onset and progression of COVID-19.

Additionally, miRNAs implicated in both COVID-19 and neurological disorders have been identified, providing insights into the mechanisms behind neurological symptoms associated with the disease.

Research Study in Abu Dhabi, UAE

To further understand the genetic and biological factors underlying COVID-19 severity, a comprehensive multi-omics dataset was generated and analyzed. The dataset included genotypes, miRNA and mRNA expression profiles, and phenotypic information derived from electronic health records (EHRs) of 259 unvaccinated COVID-19 patients in Abu Dhabi, UAE.

This systems genetic approach allowed for the identification of miRNAs associated with blood traits related to disease severity and progression. Moreover, the study revealed the impact of host genetic regulatory variation on miRNA expression traits, suggesting that the severity of COVID-19 is influenced by host genetic control of post-transcriptional events in circulating immune cells.


The role of miRNAs in the immune response to SARS-CoV-2 infection and the severity of COVID-19 is an emerging field of study. Research efforts are shedding light on the genetic and biological factors underlying disease progression and outcomes. The study conducted in Abu Dhabi, UAE, provides valuable insights into the associations between miRNA expression, genetic variations, and COVID-19 severity.

As our understanding continues to evolve, further research in diverse populations and the exploration of novel therapeutic interventions targeting miRNA regulation may pave the way for improved management and treatment of COVID-19.

reference link : https://humgenomics.biomedcentral.com/articles/10.1186/s40246-023-00494-4#Sec1



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