Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new member of the Betacoronaviridae family, responsible for the recent pandemic outbreak of COVID-19. To start exploring the molecular events that follow host cell infection, we queried VirusCircBase and identified a circular RNA (circRNA) predicted to be synthesized by SARS-CoV-2, circ_3205, which we used to probe: (i) a training cohort comprised of two pools of cells from three nasopharyngeal swabs of SARS-CoV-2 infected (positive) or uninfected (negative, UCs) individuals; (ii) a validation cohort made up of 12 positive and 3 negative samples. The expression of circRNAs, miRNAs and miRNA targets was assayed through real-time PCR. CircRNA–miRNA interactions were predicted by TarpMiR, Analysis of Common Targets for circular RNAs (ACT), and STarMir tools. Enrichment of the biological processes and the list of predicted miRNA targets were retrieved from DIANA miRPath v3.0. Our results showed that the predicted SARS-CoV-2 circ_3205 was expressed only in positive samples and its amount positively correlated with that of SARS-CoV-2 Spike (S) mRNA and the viral load (r values = 0.80952 and 0.84867, Spearman’s correlation test, respectively). Human (hsa) miR-298 was predicted to interact with circ_3205 by all three predictive tools. KCNMB4 and PRKCE were predicted as hsa-miR-298 targets. Interestingly, the function of both is correlated with blood coagulation and immune response. KCNMB4 and PRKCE mRNAs were upregulated in positive samples as compared to UCs (6 and 8.1-fold, p values = 0.049 and 0.02, Student’s t test, respectively) and their expression positively correlated with that of circ_3205 (r values = 0.6 and 0.25, Spearman’s correlation test, respectively). We propose that our results convincingly suggest that circ_3205 is a circRNA synthesized by SARS-CoV-2 upon host cell infection and that it may behave as a competitive endogenous RNA (ceRNA), sponging hsa-miR-298 and contributing to the upregulation of KCNMB4 and PRKCE mRNAs.
Highlights
Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) is an enveloped virus classified as a new member of the Coronaviridae family, Betacoronavirus genus, whose genome consists of a single stranded positive ( +) RNA molecule about 30 kilobases long [1, 2]
The best characterized functions of circular RNA (circRNA) consist in sponging microRNAs and RNA-binding proteins (RBPs) [5, 9]: in the first case, circRNAs may be typically involved in competitive endogenous RNA networks [10,11,12,13]; in the second case, circRNAs may regulate biological processes within eukaryotic cells, such as assembly of preinitiation complex (PIC) at the beginning of transcription or splicing [14, 15]
The expression of SARS-CoV-2 circRNAs 363, 368, 2667, 2670, 2685, 2795, 3058, and 3205 was assayed in a discovery cohort made of a pool of three positive samples and three UCs
Summary
Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) is an enveloped virus classified as a new member of the Coronaviridae family, Betacoronavirus genus, whose genome consists of a single stranded positive ( +) RNA molecule about 30 kilobases long [1, 2]. CircRNAs have been found aberrantly expressed in many cancers and degenerative diseases [19, 20] and are associated with several biological processes, both in physiological and pathological conditions [21,22,23,24]. Due to their intrinsic resistance to the activity of exoribonucleases and their presence in several human body fluids as well as within extracellular vesicles, circRNAs have been suggested as good candidate diagnostic and prognostic biomarkers for several diseases [25,26,27,28]
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