Downregulation of Interferon-β and Inhibition of TLR3 Expression are associated with Fatal Outcome of Severe Fever with Thrombocytopenia Syndrome

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.

Alterations of Gut Microbiome in the Patients With Severe Fever With Thrombocytopenia Syndrome

“…Severe fever with thrombocytopenia syndrome 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% ( Li et al, 2014 ; Song et al, 2017 ). In recent years, the number of SFTS cases have increased considerably in China from 511 in 2011 to nearly 1,500 cases in 2012 ( Silvas and Aguilar, 2017 ).…”

“…The severe cases could present with hemorrhagic, neurologic, multiple organs dysfunction, and even developing fatal outcome ( Sun Y. et al, 2014 ). Although recently studies had reported that dysfunction of innate immune response ( Song et al, 2017 ), cytokine storm and endothelial activation/dysfunction ( Li et al, 2017 ) were associated with SFTS, the pathogenesis of SFTS has not been fully defined.…”

The Regulation of Seventeen Inflammatory Mediators are Associated with Patient Outcomes in Severe Fever with Thrombocytopenia Syndrome

“…However, this is a rigorous prospective study which took 2 years in a representative hospital for the treatment of SFTS, 37 inflammatory mediators were detected dynamically in SFTS patients as the disease progressed. Previous study have reported that type I interferon response would contribute to viral infection 16 , and this would need to be researched in our future study.…”

“…Immune response against viral infection is believed to play an important role in its pathogenesis 10 – 12 . Previous studies have indicated that cytokines including IL-1RA, IL-6, IL-10, G-CSF, IP-10, TNF-α, IFN-γ, and MCP-1 were elevated in SFTS patients 13 – 16 .…”

Genetic and pathogenic diversity of severe fever with thrombocytopenia syndrome virus (SFTSV) in South Korea

“…To understand the differing clinical manifestations of SFTSV infections, several studies were analyzed to compare host factors such as age, cytokine profile in sera, proportions of PBMCs, and viral titers in the central nervous system (22)(23)(24)(25). However, whether the pathogenic potential of different SFTSV strains varies remains unclear.…”