Abstract
Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease with high mortality and increasing prevalence in the East Asia. Though the etiological agent has been identified as a novel Bunyavirus, cellular mechanisms of viral pathogenesis and host immune response to SFTS virus infection remain unknown. A comprehensive study was conducted on a cohort of 70 patients on clinical manifestations, viral loads, modulation of cytokines, serum interferon level, immune related gene expression in peripheral blood cells, and dynamic changes of circulating dendritic cells during the acute phase of SFTSV infection. We found that high level viremia, reduced platelets, coagulation dysfunction, multi-organ injuries, elevated IL-6 and TNF-α were closely associated with the aggravation of SFTS. In addition, we demonstrated strong correlations between disease severity and the decline of serum IFN-β and IL-1β level, reduction of myeloid dendritic cells (mDCs) and suppressed Toll like receptor 3 expression in monocytes and mDCs. In general, dysfunction of innate immune response and cytokine storm are both involved in the pathogenesis of SFTS. Reduction of myeloid DCs contributes to the fatal outcome of SFTS virus infection, and the regulation of TLR3 could probably be the mechanism.
Highlights
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized with high fever, thrombocytopenia, leukocytopenia, gastrointestinal symptoms, hemorrhage, and multiple organ failure, with high fatalities ranging from 12% to 30%1–3
In the current study, taking the advantage of a relatively large patient cohort (70 Severe Fever with Thrombocytopenia Syndrome (SFTS) patients with various clinical manifestations), we conducted a comprehensive study focusing on the complex relationship among serum interferon level, viral load, pro-inflammatory cytokines and peripheral dendritic cells, and attempted to elucidate the roles of innate immunity and the regulatory network involving in SFTS virus infection
Our results demonstrated that the TLR3 expressions by myeloid dendritic cells (mDCs) (Fig. 5B) and monocytes (Fig. 5F) in deceased group were gradually downregulated during the acute phase, and significantly declined as compared with the survived group at the third week (p = 0.048, 0.04 respectively), TLR3 expression in the deceased group was significantly higher than the survived group at the first week (p = 0.003, 0.002, respectively)
Summary
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized with high fever, thrombocytopenia, leukocytopenia, gastrointestinal symptoms, hemorrhage, and multiple organ failure, with high fatalities ranging from 12% to 30%1–3. Recent research on the pathogenesis of SFTS virus infection mainly focused on two aspects: cytokine storm-mediated immune activation and mechanisms of impairment of innate immune response. Sun et al reported that SFTS virus-induced cytokine storm was characterized by a drastic increase of IL-1RA, IL-6, IL-10, G-CSF, IP-10 and MCP-1 in the acute phase of infection, indicating that the immune activation contributes to the pathogenesis of SFTS6. In the current study, taking the advantage of a relatively large patient cohort (70 SFTS patients with various clinical manifestations), we conducted a comprehensive study focusing on the complex relationship among serum interferon level, viral load, pro-inflammatory cytokines and peripheral dendritic cells, and attempted to elucidate the roles of innate immunity and the regulatory network involving in SFTS virus infection
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