Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate between 12 and 30%, which is caused by a tick-born bunyavirus, SFTS virus (SFTSV). Type I interferon receptor-deficient (IFNAR KO) mice, but not wild type (WT) mice, have been established as a lethal animal model of SFTSV infection, indicating that type I interferon (IFN-I) is necessary for controlling SFTSV replication. However, the mechanism of IFN-I production and the pathogenesis of SFTSV infection have not been identified yet.
To reveal this, we first generated bone-marrow (BM) chimeric mice. The lethally irradiated WT and IFNAR KO mice were reconstituted with either WT or IFNAR KO BM, respectively. The presence of IFNAR in hematopoietic cells contributed to the resistance against SFTSV infection even when non-hematopoietic cells lacked IFNAR. Contrarily, IFNAR deficiency in hematopoietic cells increased the severity of SFTSV infection and caused lethality, showing that hematopoietic cells respond to IFN-I and thereby promote the antiviral response.
Next, to identify the key signaling pathway for the IFN-I production, we challenged innate immunity-related molecules, including IPS-1 and MyD88, deficient mice with SFTSV. IPS-1 deficiency, not MyD88, abolished IFN-I and inflammatory cytokine production, suggesting that IPS-1 signaling is the major source of IFN-I from hematopoietic cells. However, unexpectedly all infected IPS-1 deficient mice survived and the viral load in them was comparable to that in WT mice. We assume that IPS-1-dependent-cytokine storm promotes the viral spread and lethality, because infected IFNAR KO mice highly produced various cytokines.
Altogether, these results indicate that hematopoietic cells promote IPS-1-dependent-antiviral response against SFTSV infection. We propose that dysregulation of IPS-1 signaling causes lethal cytokine storm related to the pathogenesis of SFTSV infection and restricted activation of IPS-1 pathway is beneficial to the host.