RNA transcriptome analysis of platelets revealed altered platelet responses and the mechanism of thrombocytopenia in SFTS

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral hemorrhagic fever disease caused by infection with Dabie bandavirus (SFTS virus, SFTSV). Thrombocytopenia is the primary clinical feature of SFTS and is significantly associated with disease severity. However, the pathological mechanism of thrombocytopenia in SFTS remains unclear. Methods Platelets purified from SFTS patients were subjected to RNA transcriptome analyses. Differentially expressed genes (DEGs) in the platelets of deceased and surviving patients were identified, and their functions and transcription levels were characterized. DEGs related to cell death were compared with the platelets of COVID-19 and dengue fever patients. The percentage of platelets positive for biomarkers of pyroptosis, apoptosis, necroptosis, autophagy, and ferroptosis was determined by flow cytometry. RNA transcriptome analyses were also performed with platelets purified from nonlethal SFTSV infection model mice. DEGs representing the functional changes in mouse platelets were characterized, and platelet death was also investigated. Functional platelet changes in SFTS patients and SFTSV-infected mice were compared to determine the different mechanisms underlying thrombocytopenia in humans and mice. Results Platelet transcriptome analyses revealed altered platelet functioning in SFTS patients and suggested an active platelet response in surviving patients but not in fatal patients. Enhanced neutrophil activation, interferon (IFN) signaling, and the virus life cycle were common platelet responses in SFTS. The increased histone methylation and impaired vesicle organization in platelets may be related to the fatal outcome, while the enhanced protein transport to membrane and RNA catabolic process may contribute to disease recovery. Moreover, SFTSV infection resulted in platelet loss via pyroptosis, apoptosis, necroptosis, and autophagy but not ferroptosis. Unlike platelets in SFTS patients, platelets in SFTSV-infected mice play a role mainly in regulating adaptive immunity, and platelet death in mice was not as severe as that in humans. Conclusions This study revealed altered platelet functioning in response to SFTSV infection and the mechanisms of thrombocytopenia in humans, which are different from those in mice infected with SFTSV. The results deepen our understanding of the pathogenesis of thrombocytopenia in SFTS and provides insights for subsequent studies on SFTS pathogenesis and the development of novel intervention strategies.