SFTSV-encoded microRNA-like small RNA as prognostic biomarkers in severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is a highly fatal infectious disease caused by the SFTS virus (SFTSV). Reliable prognostic biomarkers are essential for early intervention, yet specific markers for SFTSV infection remain unidentified. In this study, we identified SFTSV-encoded microRNA-like small RNAs (milRNAs) in patients' sera and evaluated their potential as prognosis biomarker. A multi-phase study involving 170 laboratory-confirmed SFTS patients, 40 patients with other infection and 80 healthy controls was conducted. Small RNA deep sequencing was performed, followed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and TA cloning for individual validation. The expression dynamics of identified milRNAs were analyzed across different disease stages, and their prognostic potential was assessed using Kaplan-Meier survival analysis and Cox proportional hazards regression. Three SFTSV-encoded milRNAs - SFTSV-S-1480 (S-1480), SFTSV-M-692 (M-692), and SFTSV-L-4706 (L-4706) - were significantly elevated in the sera of severe patients but were nearly undetectable in mild cases and healthy controls. Their expression levels increased notably during the multiple organ dysfunction (MOD) stage, correlating with disease progression. Patients with higher milRNA expression had significantly shorter survival compared to those with lower expression. Receiver operating characteristic (ROC) curve analysis demonstrated that the three-milRNA panel outperformed traditional blood immune cell indicators in predicting disease severity. Our study identifies a panel of three SFTSV-encoded milRNAs as novel prognostic biomarkers for SFTS. Their strong correlation with disease progression and clinical outcomes suggests their potential utility for early risk stratification and targeted intervention.