Activation of the NLRP3 inflammasome and elevation of interleukin-1β secretion in infection by sever fever with thrombocytopenia syndrome virus

Zhifeng Li, Jianli Hu, Changjun Bao, Chengfeng Gao, Nan Zhang, Carol J. Cardona, Zheng Xing

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Article number2573
JournalScientific reports
Volume12
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by funding from the National Nature Science Foundation of China ( http://www.nsfc.gov.cn ) with grants No. 81971923 to Z.X. and 81703284 to Z.L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Animals
  • Bunyaviridae Infections/complications
  • Case-Control Studies
  • Humans
  • Inflammasomes/immunology
  • Interleukin-1beta/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein/genetics
  • Phlebovirus/isolation & purification
  • Severe Fever with Thrombocytopenia Syndrome/etiology
  • Virus Replication

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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