Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging phlebovirus that causes a hemorrhagic fever known as the severe fever with thrombocytopenia syndrome (SFTS). Inflammasomes are a molecular platform that are assembled to process pro-caspase 1 and subsequently promote secretion of interleukin (IL)-1β/IL-18 for proinflammatory responses induced upon infection. We hypothesize that inflammasome activation and pyroptosis induced in SFTS results in elevated levels of IL-1β/IL-18 responsible for high fever and hemorrhage in the host, characteristic of SFTS. Here we report that IL-1β secretion was elevated in SFTS patients and infected mice and IL-1β levels appeared to be reversibly associated to disease severity and viral load in patients’ blood. Increased caspase-1 activation, IL-1β/IL-18 secretion, cell death, and processing of gasdermin D were detected, indicating that pyroptosis was induced in SFTSV-infected human peripheral blood monocytes (PBMCs). To characterize the mechanism of pyroptosis induction, we knocked down several NOD-like receptors (NLRs) with respective shRNAs in PBMCs and showed that the NLR family pyrin domain containing 3 (NLRP3) inflammasome was critical for processing pro-caspase-1 and pro-IL-1β. Our data with specific inhibitors for NLRP3 and caspase-1 further showed that activation of the NLRP3 inflammasome was key to caspase-1 activation and IL-1β secretion which may be inhibitory to viral replication in PBMCs infected with SFTSV. The findings in this study suggest that the activation of the NLPR3 inflammasome and pyroptosis, leading to IL-1β/IL-18 secretion during the SFTSV infection, could play important roles in viral pathogenesis and host protection. Pyroptosis as part of innate immunity might be essential in proinflammatory responses and pathogenicty in humans infected with this novel phlebovirus.
Highlights
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging phlebovirus that causes a hemorrhagic fever known as the severe fever with thrombocytopenia syndrome (SFTS)
Earlier studies revealed that SFTSV infection in humans induced expression of IL-1β, a proinflammatory cytokine, which was in significantly higher levels in the sera of severely and fatally affected patients than it was in mildly ill patients, indicating that IL-1β might contribute to a cytokine storm and deteriorating pathogenicity[17]
We analyzed the induction of IL-1β in SFTS patients and mice infected with SFTSV and our data revealed a mechanism by which an NLR family pyrin domain containing 3 (NLRP3) inflammasome was activated, resulting in the processing of pro-caspase-1 and secretion of IL-1β/IL-18 in human peripheral blood monocytes (PBMCs)
Summary
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging phlebovirus that causes a hemorrhagic fever known as the severe fever with thrombocytopenia syndrome (SFTS). Increased caspase-1 activation, IL-1β/IL-18 secretion, cell death, and processing of gasdermin D were detected, indicating that pyroptosis was induced in SFTSV-infected human peripheral blood monocytes (PBMCs). The findings in this study suggest that the activation of the NLPR3 inflammasome and pyroptosis, leading to IL-1β/IL-18 secretion during the SFTSV infection, could play important roles in viral pathogenesis and host protection. We analyzed the induction of IL-1β in SFTS patients and mice infected with SFTSV and our data revealed a mechanism by which an NLRP3 inflammasome was activated, resulting in the processing of pro-caspase-1 and secretion of IL-1β/IL-18 in human PBMCs. We further showed that SFTSV induced IL-1β secretion and pyroptosis which might restrict viral replication in cell cultures and mice, suggesting that the NLRP3 inflammasome may exert antiviral and host protective activities against SFTSV
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