IL-27–mediated hematopoietic dysregulation exacerbates disease severity in severe fever with thrombocytopenia syndrome virus infection

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening tick-borne viral infection characterized by high fever, thrombocytopenia, and severe inflammation, with no effective treatments now available. Through comprehensive analysis of bone marrow and peripheral blood mononuclear cells in mice and from patients with SFTS, we identified interleukin-27 (IL-27) as a key driver of disease progression. Elevated IL-27 levels promoted emergency hematopoiesis and impaired protective B cell development and antibody production, resulting in worsened inflammation and ineffective viral control. Inducing IL-27 expression in monocytes and B cells triggered a vicious inflammatory cycle, exacerbating the severity of SFTS. Neutralizing IL-27 in a lethal mouse model of SFTS improved survival, reduced viral loads, and restored antiviral immunity, highlighting IL-27 as a promising therapeutic target for SFTS.