Upregulation of distinct miRNAs in SARS-CoV-2 infected individuals: A differential signature of circulating miRNAs

COVID-19 exhibits a broad clinical spectrum, from asymptomatic to severe cases, underscoring the need for molecular biomarkers to support surveillance and early intervention. Here, we profiled circulating microRNAs (miRNAs) in plasma samples from individuals with asymptomatic/mild COVID-19 and uninfected controls. Seven miRNAs were significantly upregulated in infected patients (miR-126, miR-146b-5p, miR-223-5p, miR-144-3p, miR-22, miR-146a, and miR-30c). ROC curve analysis revealed heterogeneous diagnostic performance: miR-30c achieved the highest overall discriminatory accuracy (AUC = 0.771) with maximum sensitivity (100.0%), while miR-126 provided the highest specificity (100.0%, AUC = 0.763). Other miRNAs, including miR-146b-5p, miR-223-5p, miR-146a, miR-144-3p, and miR-22, showed intermediate accuracy (AUCs 0.684-0.719), whereas miR-21-5p and miR-155 displayed limited discriminatory power (AUCs 0.606 and 0.517, respectively). Predictive interaction network analysis indicated that the upregulated miRNAs target key immune-related genes (CXCL12, IRAK1, TRAF6, STAT1, JAK1, NOTCH1, SMAD4, and BCL2L11), and functional enrichment revealed convergence with transcriptomic profiles from SARS-CoV-2-infected Calu-3 cells, including FOXO3, JAK2, STAT1, and SIRT1. Collectively, these findings point out for potential miRNA signatures associated with mild, non-hospitalized COVID-19 in a predominantly vaccinated cohort but requiring further investigation as molecular markers of early host responses in larger, independent, and clinically diverse cohorts. ImportanceCOVID-19 produces a wide range of outcomes, from no symptoms to severe illness, and clinicians still lack simple molecular tools to help identify infections or anticipate a patients course early in the disease. miRNAs are small molecules circulating in blood that help control gene activity, and because their levels change during infection, they can be considered potential biomarkers candidates for blood-based tests. Here, we measured nine circulating miRNAs in individuals with mild COVID-19 and in uninfected individuals, thus finding that seven of them were consistently higher in infected patients, with some distinguishing the two groups quite well. This study also links these miRNAs to genes involved in the immune response against SARS-CoV-2. Our findings, generated in a modestly sized cohort, support further investigation of blood-based microRNA panels as potential candidates to help identify infection and clarify early host responses to SARS-CoV-2, pending validation in larger and more clinically diverse cohorts.