COVID-19 presents a wide clinical spectrum from asymptomatic to severe disease, creating a need for molecular biomarkers that can support surveillance and early intervention. The authors aimed to identify circulating microRNA (miRNA) signatures in plasma that differentiate individuals with asymptomatic or mild SARS-CoV-2 infection from uninfected controls. The focus was on non-hospitalized patients within a predominantly vaccinated cohort to characterize early host responses.
Researchers profiled circulating miRNAs in plasma samples collected from individuals with asymptomatic or mild COVID-19 and from uninfected control subjects. This work is reported as a preprint; methods and full cohort characteristics are described in the source but specific sample sizes, collection timing, and analytical platforms were not detailed in the abstract. The cohort is noted to be predominantly vaccinated and composed of non-hospitalized cases.
Seven miRNAs were identified as significantly upregulated in plasma from infected individuals compared with controls. These are miR-126, miR-146b-5p, miR-223-5p, miR-144-3p, miR-22, miR-146a, and miR-30c. Two commonly studied inflammatory miRNAs, miR-21-5p and miR-155, were assessed but demonstrated limited discriminatory power in this cohort.
Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory accuracy of individual miRNAs. The reported performances were heterogeneous:
miR-30c achieved the highest overall discriminatory accuracy with an area under the curve (AUC) of 0.771 and showed maximum sensitivity (100.0%) in this dataset.
miR-126 provided the highest specificity among tested miRNAs (100.0%) with an AUC of 0.763.
miR-146b-5p, miR-223-5p, miR-146a, miR-144-3p, and miR-22 showed intermediate accuracy with AUCs ranging from 0.684 to 0.719.
miR-21-5p and miR-155 had limited discriminatory power (AUCs of 0.606 and 0.517, respectively).
These results indicate that certain circulating miRNAs can distinguish mild/asymptomatic SARS-CoV-2 infection from uninfected status with variable sensitivity and specificity, but no single marker reached diagnostic perfection.
Predictive interaction network analysis was performed to identify putative gene targets of the upregulated miRNAs. The analysis indicated that these miRNAs target key immune-related genes, including CXCL12, IRAK1, TRAF6, STAT1, JAK1, NOTCH1, SMAD4, and BCL2L11. These genes are involved in innate and adaptive immune signaling and may mediate host responses to viral infection.
Functional enrichment analysis revealed convergence between the predicted miRNA targets and transcriptomic profiles from SARS-CoV-2–infected Calu-3 cells. Specific genes highlighted in this overlap included FOXO3, JAK2, STAT1, and SIRT1, suggesting that the circulating miRNA changes observed in plasma may reflect molecular pathways perturbed by SARS-CoV-2 infection in epithelial cells or systemic immune responses.
The authors emphasize that the study cohort comprised predominantly vaccinated, non-hospitalized individuals with asymptomatic or mild disease. As a preprint report, the abstract does not provide full methodological detail or sample size metrics. The findings therefore require validation in larger, independent, and clinically diverse cohorts, including hospitalized and unvaccinated populations, to determine reproducibility, generalizability, and clinical utility.
Additionally, while predictive network and enrichment analyses link upregulated miRNAs to key immune genes and infected-cell transcriptomes, these are in silico inferences that require experimental validation to confirm direct miRNA-target interactions and functional consequences.
This study reports a distinct circulating miRNA signature associated with mild, non-hospitalized SARS-CoV-2 infection in a predominantly vaccinated cohort. Seven miRNAs (miR-126, miR-146b-5p, miR-223-5p, miR-144-3p, miR-22, miR-146a, and miR-30c) were significantly upregulated, with miR-30c showing the highest sensitivity and miR-126 the highest specificity by ROC analysis. Predicted targets link these miRNAs to immune-related genes and to transcriptional changes observed in SARS-CoV-2–infected cell models. The authors conclude that these circulating miRNAs are candidate molecular markers of early host response, but stress the need for further investigation and independent validation before consideration for clinical surveillance or diagnostic use.