Journal of virology 2018 04 11() pii 10.1128/JVI.02246-17
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family , the SFTS virus (SFTSV). Wild type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1) mice have been established as non-lethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production and the factors causing the lethal disease are not well understood. Using bone marrow chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival from lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by the deletion of signaling molecules IPS-1 and MyD88, essential for RLRs and TLRs signaling, respectively. However, IPS-1 MyD88 mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLRs and TLRs signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines causing the lethal disease. SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12-30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that the lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat severe SFTS patients. Furthermore, this study may help the investigation of other tick-borne viruses.