The Role of Small Non-Coding RNAs in SARS-CoV-2 Infection


The outbreak of pneumonia that originated in Wuhan, China, at the end of 2019 marked the beginning of a global public health crisis. This mysterious disease was later attributed to a novel coronavirus, formally named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

This virus is the causative agent of the infamous coronavirus disease 2019 (COVID-19), which presents a range of symptoms including respiratory distress, fever, cough, fatigue, pneumonia, and muscle pain.

As scientists worldwide grappled with understanding the pathogenesis and pathophysiology of COVID-19, they recognized the need to delve deeper into the transcriptomic changes induced by SARS-CoV-2, especially within the non-coding RNA layer.

In this article, we embark on a comprehensive exploration of the relationship between SARS-CoV-2 infection and the altered accumulation of endogenous small non-coding RNAs (sncRNAs or sRNAs). These sncRNAs are ubiquitous in all domains of life, from prokaryotes to eukaryotes, and they play pivotal roles in regulating gene expression.

Typically, sncRNAs are RNA molecules shorter than 50 nucleotides, encompassing microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), transfer RNA-derived fragments (tsRNAs), small nuclear RNAs (snsRNAs), small nucleolar RNAs (sdRNAs), and trimmed forms of miRNAs known as tiny RNAs (tyRNAs). Although once considered byproducts of RNA metabolism, these non-canonical sncRNAs are now recognized for their functional significance.

Biogenesis of sncRNAs

The biogenesis of miRNAs involves the processing of structured RNA precursors, typically through ribonuclease (RNase) III enzymes like Drosha and Dicer.

On the other hand, piRNAs arise from linear RNA precursors independently of Dicer and Drosha activity. TsRNAs are classified into two main categories: tRNA-derived fragments (tRFs) and tRNA halves, each generated by distinct cleavage mechanisms. SdRNAs are predominantly derived through the classic miRNA biogenesis pathway, involving the action of Drosha and Dicer, with variations in length depending on the parental small nucleolar RNA (snoRNA) type. TyRNAs, a relatively recent discovery, result from the trimming of Argonaute (AGO)-associated full-length miRNAs into 14-nt or shorter RNA molecules.

Functions of sncRNAs

The functions of miRNAs and piRNAs primarily hinge on their complementarity to RNA and DNA targets, leading to RNA silencing, translation repression, or transcriptional repression via AGO/PIWI family proteins. TsRNAs have garnered attention for their accumulation in response to stress conditions, including viral infections, cancer, and starvation.

Studies indicate that tsRNAs can enter the RNA interference pathway and interact with RNA-binding proteins and ribosomes. SdRNAs mainly act as molecular guides for AGO2, with perfect complementarity leading to target RNA cleavage and imperfect binding resulting in translation repression. TyRNAs are implicated in an alternative RNA cleavage pathway, potentially enhancing the slicing activity of AGO3.

A Comprehensive Study of SncRNAs in SARS-CoV-2 Infection

In our research, we undertook an integrative study of the sncRNA landscape, analyzing multiple clinical samples collected from COVID-19 patients with varying degrees of symptom severity and at different stages of infection. Our study builds upon previous research that hinted at an association between SARS-CoV-2 infection and disturbances in host sncRNAs. However, our work offers enhanced statistical power and a more detailed clinical assessment.

Our findings provide compelling evidence that SARS-CoV-2 infection not only disrupts the accumulation of host miRNAs and tsRNAs but also significantly alters the levels of specific sdRNAs and tyRNAs. This novel insight underscores the crucial role played by the regulatory RNA layer in the infection process and enhances our understanding of SARS-CoV-2’s mode of action.


Numerous studies have investigated the impact of SARS-CoV-2 infection on the small non-coding RNA (sncRNA) landscape in humans. However, these efforts have predominantly focused on analyzing alterations in circulating miRNA profiles recovered from blood or plasma. In this study, we took a broader approach, conducting an integrative analysis to assess the global impact of SARS-CoV-2 infection on various regulatory RNAs within human cells. We examined nasopharyngeal samples from COVID-19 patients with varying disease severity and at different stages of infection. Our findings reveal a significant imbalance in diverse sdRNAs, miRNAs, tsRNAs, and tyRNAs associated with SARS-CoV-2 infection.

miRNAs in SARS-CoV-2 Infection

Our results align with early studies demonstrating that SARS-CoV-2 infection triggers a robust host miRNA response. This miRNA response holds potential for enhancing COVID-19 detection and patient management. Of particular interest is the hsa-let-7 family, which exhibited significant down-regulation in COVID-19 patients. The let-7 family, highly conserved across species, plays essential roles in regulating critical physiological processes.

Recent research has suggested that hsa-let-7b may be involved in regulating key receptors for SARS-CoV-2 entry, namely Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4). Furthermore, computational predictions have indicated that hsa-let-7 may target the SARS-CoV-2 genome and genes associated with immune response pathways. Our findings reinforce the connection between hsa-let-7 and SARS-CoV-2 infection, as we observed its down-regulation across different stages and disease intensities.

Additionally, hsa-miR-182 emerged as a down-regulated miRNA strongly associated with infection. This observation is noteworthy, as previous analyses of infection-associated miRNAs have mainly been conducted using blood or plasma samples. Computational studies have suggested that the hsa-miR-182 family may recognize the SARS-CoV-2 genome as a potential target, potentially influencing host susceptibility to infection. This finding underscores the importance of analyzing nasopharyngeal samples to uncover miRNAs that might not be evident in other sample types.

tsRNAs: A Dynamic Response to SARS-CoV-2

Recent research has reported differential expression of tsRNAs in various sample types from COVID-19 patients. Our results corroborate these findings, emphasizing the significant alteration of tsRNA expression in response to SARS-CoV-2 infection. Interestingly, sequences derived from Glu- and Gly-tRNA precursors were the most abundant in COVID-19 patients, with Glu-tsRNAs predominant in severe infections at both early and late stages.

Gly-tsRNAs, on the other hand, were more abundant in moderate cases during the early stages of infection. Notably, 5′ variants of tsRNAs dominated our results, in contrast to recent findings that highlighted the accumulation of 3′ variants in severe cases. These differences suggest that the specific processing of tsRNAs and the class of tsRNA detected may be related to disease severity, infection stage, and the type of sample analyzed.

While the precise role of tsRNAs during SARS-CoV-2 infection remains unknown, it has been proposed that certain tRNA-derived RNAs with siRNA-like properties may target host transcripts to favor viral replication, similar to mechanisms observed in other viral infections.

sdRNAs and tyRNAs: Emerging Players in SARS-CoV-2 Pathogenesis

The functional relevance of sdRNAs is currently unclear, but their abundance suggests yet-to-be-explored regulatory roles. Our results indicate differential expression of sdRNAs in response to SARS-CoV-2 infection, with sdRNAs derived from snoRNA C/D-box precursors being predominant. While previous studies have linked sdRNAs to various pathological conditions, our RNA-Seq results provide pioneering evidence of their association with SARS-CoV-2 infection.

TyRNAs, an emerging class of sncRNAs, had not previously been associated with SARS-CoV-2 infection. Intriguingly, our findings revealed an up-regulation of tyRNAs as the predominant response to infection, indicating an unexplored layer in the host-virus interaction.

To date, tyRNAs have been primarily linked to neurodegenerative diseases, making it challenging to draw conclusions about their role in SARS-CoV-2 infection. Further investigation is warranted to uncover the functional significance of tyRNAs in this context.

Implications and Future Directions

In summary, our study offers a comprehensive view of the sncRNA signature in COVID-19 patients with varying disease severity and at different stages of infection. This information holds the potential to identify valuable biomarkers for diagnosis and prognosis. Moreover, understanding the regulatory pathways involving sncRNAs may open new avenues for innovative therapeutic and prophylactic strategies in the fight against SARS-CoV-2. Further research is essential to elucidate the mechanisms underlying the sncRNA-mediated response to SARS-CoV-2 and its potential as a target for intervention and management of COVID-19.


The COVID-19 pandemic has prompted a global scientific endeavor to decipher the intricacies of SARS-CoV-2 infection. The emergence of small non-coding RNAs as key players in the host-virus interaction opens new avenues for research and potential therapeutic strategies.

As we continue to unravel the complexities of this viral infection, understanding the interplay between sncRNAs and SARS-CoV-2 may hold the key to mitigating its impact and ultimately developing effective antiviral treatments. This comprehensive study serves as a crucial step towards that goal, shedding light on the hitherto unexplored RNA-based network in COVID-19 pathogenesis.

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