<p>Raw data of figures.</p>

SFTSV, a tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), exhibits symptoms such as thrombocytopenia, leukocytopenia, hemorrhage, disseminated intravascular coagulation, and even multiple-organ failure. Nevertheless, the underlying pathogenic pathways of this disease remain poorly understood. In this study, by utilizing a lethal mouse model of IFNAR−/− mice, we discovered that complement hyperactivation occurs in the spleen, and the spleen serves as a source of the central complement component C3 in SFTSV-infected mice. Infection of spleen stromal fibroblastic reticular cells with SFTSV significantly induces intracellular complement pathways through a type I IFN-independent manner and generates the active component C3a through the alternative pathway. The transcription of C3 and complement factor B (Cfb) in SFTSV-infected fibroblastic reticular cells is regulated by C/EBP-β. Administration of a C3aR antagonist leads to a reduction in virus load and the inflammatory response, alleviates spleen injury, and prolongs the survival time in IFNAR-/- mice. Collectively, our findings suggest that targeted complement therapy holds potential for the intervention of severe SFTS.