Respiratory transmission potential of severe fever with thrombocytopenia syndrome bunyavirus: evidence from intranasal exposure in a humanized mouse model

Severe Fever with Thrombocytopenia Syndrome Bunyavirus (SFTSV) is a highly lethal pathogen with expanding endemic regions in Asia. While primarily transmitted by ticks, recent evidence suggests potential airborne transmission, raising significant public health concerns. This study investigates the potential for respiratory transmission and pathogenesis using humanized NCG mice inoculated with SFTSV via subcutaneous injection challenge (SIC) or intranasal drop challenge (IDC). Both groups demonstrated rapid systemic dissemination, marked by viremia, weight loss, and multi-organ injury, with hemorrhagic manifestations observed in high-dose infection groups. Histopathological evaluations revealed lung pathology in the intranasal drop challenge mice, including extensive alveolar disruption and inflammatory cell infiltration. Transcriptomic analyses further confirmed that respiratory route inoculation resulted in heightened expression of inflammatory signalling pathways such as IL-17 and NF-κB, potentially contributing to severe local immunopathology. Subcutaneous infection provoked an earlier systemic immune response, with significant upregulation of antigen-processing genes in peripheral blood mononuclear cells. Nevertheless, both routes ultimately culminated in widespread injury to the liver, spleen, kidney, highlighting the systemic nature of SFTSV pathogenesis. These findings underscore the need for preventive strategies addressing respiratory spread.