Severe fever with thrombocytopenia syndrome virus infection of the male reproductive tract induces pathology and inflammation.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus causing severe systemic infection with high mortality rates. Previously, SFTSV RNA was reported in the semen of infected patients, but whether SFTSV infects the male reproductive tract remains unclear. Here we demonstrate that SFTSV exhibits broad tropism for male reproductive organs in mice, resulting in low sperm count and local inflammation. SFTSV infects Leydig cells in the testis, triggering apoptosis, pyroptosis and inflammation, thereby disrupting testosterone production. Single-cell RNA sequencing identified infiltration of CCR2+ and SPP1+ macrophages expressing S100A4, a key driver of epididymal hyperinflammation and fibrosis. An S100A4 inhibitor reduced pathology and mortality in infected mice. Potential male-to-female sexual transmission risk was observed in mice. In infected patients, viral shedding in semen correlated with disease severity and spermatogenic dysfunction, with viral persistence lasting nearly 3 months after symptom onset. These findings suggest a potential risk of sexual transmission and adverse effects on male reproductive health.