Study finds SARS-CoV-2 infection caused significant changes in the levels of stress associated small RNAs

The coronavirus disease 2019 (COVID-19) pandemic has been caused by a highly infectious RNA virus, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This ongoing pandemic has immensely affected the global economy and healthcare system. SARS-CoV-2 symptoms could be mild, moderate, severe, or critical.

Study: SARS-CoV-2 Causes a Significant Stress Response Mediated by Small RNAs in the Blood of COVID-19 Patient. Image Credit: creativeneko/Shutterstock

Background

Scientists have reported that approximately 28% of deaths occurred due to cytokine storms and sepsis induced by SARS-CoV-2 infection. Previous studies associated with molecular pathogenesis and pathophysiology of COVID-19 infection revealed the occurrence of renin-angiotensin-aldosterone system (RAAS) dysregulation, hyper inflammation, hypoxia, cytokine storm, thrombosis, and endotheliopathy.

Some individuals infected with SARS-CoV-2 have suffered dysfunctional hyperinflammatory responses with prolonged fevers and high levels of inflammatory marker. Severely infected COVID-19 patients revealed an elevated concentration of proinflammatory cytokines and chemokines. Another subset of severely infected COVID-19 patients suffered a dysfunctional hyperinflammatory response without fevers and multiple organ failure. A previous study reported considerable changes in C-reactive protein (CRP) levels in sera of critically ill COVID-19 patients.

Promising COVID-19 therapeutics using small molecules

Even though many studies have focused on the mechanisms of infection, COVID-19 pathogenesis, and disease processes are not well understood. Several studies have reported the role of microRNAs (miRNAs) in the process of virus infection. miRNAs are a type of small non-coding RNA (sncRNA) whose size varies between 18 and 22 nucleotides.

They damage the receptor genes, which assist virus entry to the host cell, by promoting degradation or translational inhibition of target transcripts by binding to the 3' UTR (untranslated region). miRNAs have several other functions that include regulating virus replication or translation cofactors, affecting initial or adaptive immune genes, silencing genes, and promoting cell apoptosis. 

Previous studies have shown abnormal expression of miRNAs in viral diseases, such as enterovirus and chronic hepatitis. These reports have laid a foundation for the future clinical application of miRNAs. Recently, clinicians were suggested to treat COVID-19 infected patients with a 'nose cocktail' of miRNA. Besides miRNA, tRNA-derived small RNAs (tsRNAs) have been reported to be stable and functional small molecules produced by reprocessing the precursors or mature transcripts of tRNA. The levels of tsRNAs correlate to stress conditions, such as temperature, starvation, virus infection, and cancer. 

Recent studies have reported that tsRNAs can protect genomes by targeting primer-binding sites (PBSs) of endogenous retroviruses (ERVs) or human T cell leukemia virus type 1 (HTLV1). In somatic cells, the two most abundantly found small RNAs are miRNAs and tsRNAs, and both are related to virus infection and the immune response. There is a gap in research about the functions of these small RNAs post-SARS-CoV-2 infection. 

A new study

Recently, scientists have addressed the above-stated research gap and conducted high-throughput sequencing to identify the repertoire of small RNAs expressed in the blood of patients with moderate to severe COVID-19 infection. They compared the results with a control group that comprised healthy individuals. This study is forthcoming in Molecular Therapy: Nucleic Acid. In this study, researchers described the effect of significant changes of small RNAs in the post-transcriptional regulatory network.

The authors revealed that both miRNAs and tsRNAs are changed owing to stress response and downstream pathway changes (e.g., immunity and inflammation). This study reported that sncRNA-induced stress response is a common pathway in all cells and, thereby, the effect of these stress-related small RNAs would be experienced by most cell types.

However, scientists have studied the effect of small RNA on whole blood samples. In the future, the effect of small RNAs could be studied based on individual cell types. Additionally, the expression and function of small RNAs require further validation to determine their role and mechanism in the development of COVID-19 infection.

Main findings

Scientists reported that the expression profile of miRNAs could be used to differentiate among different groups of COVID-19 patients accurately. They further reported that miRNAs regulate 60% of all protein-coding genes at the post-transcriptional level. This implies that miRNAs play a crucial role in cell development, differentiation, and immune processes.

Interestingly, researchers found the presence of several HI-DOWN miRNAs in the blood of SARS-CoV-2 infected patients that have antiviral functions. For instance, miR-181 can bind to the receptor gene CD163, affecting virus entry. Additionally, miR-130 can regulate HCV cofactors and affect its viral replication. This study also reported that miR-29 is an antiviral factor produced by IL-21 in CD4 T cells.

The findings of this study are in line with previous studies that revealed miR-335 directly regulates the stress response. Researchers have also highlighted that miRNAs are enriched in the ER stress pathway. The authors believe that miRNA-target genes should regulate the specificity, timing, and severity of the cell response to SARS-CoV-2 infection stresses.

Conclusion

The current study revealed that the small RNAs detected in the blood of COVID-19 patients are predominantly produced by the human genome and not by the SARS-CoV-2 genome. The authors suggested that SARS-CoV-2 infection causes considerable changes in the stress level associated with small RNAs and their functions. This study provides a potential idea of developing a new COVID-19 therapeutic intervention by regulating small RNA levels or activities.