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SFTSV Infection Induces BAK/BAX-Dependent Mitochondrial DNA Release to Trigger NLRP3 Inflammasome Activation.
- Source :
-
Cell reports [Cell Rep] 2020 Mar 31; Vol. 30 (13), pp. 4370-4385.e7. - Publication Year :
- 2020
-
Abstract
- Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus that carries a high fatality rate of 12%-50%. In-depth understanding of the SFTSV-induced pathogenesis mechanism is critical for developing effective anti-SFTS therapeutics. Here, we report transcriptomic analysis of blood samples from SFTS patients. We observe a strong correlation between inflammatory responses and disease progression and fatal outcome. Quantitative proteomic analysis of SFTSV infection confirms the induction of inflammation and further reveals virus-induced mitochondrial dysfunction. Mechanistically, SFTSV infection triggers BCL2 antagonist/killer 1 (BAK) upregulation and BAK/BCL2-associated X (BAX) activation, leading to mitochondrial DNA (mtDNA) oxidization and subsequent cytosolic release. The cytosolic mtDNA binds and triggers NLRP3 inflammasome activation. Notably, the BAK expression level correlates with SFTS disease progression and fatal outcome. These findings provide insights into the clinical features and molecular underpinnings of severe SFTS, which may aid in patient care and therapeutic design, and may also be conserved during infection by other highly pathogenic viruses.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Animals
Bunyaviridae Infections genetics
Bunyaviridae Infections virology
Cell Line
Disease Models, Animal
Disease Progression
Female
Humans
Inflammation genetics
Interleukin-1beta metabolism
Mice, Inbred C57BL
Mitochondria metabolism
Mitochondria pathology
Models, Biological
Myeloid Differentiation Factor 88 metabolism
NF-kappa B metabolism
Reactive Oxygen Species metabolism
Signal Transduction
Toll-Like Receptor 8 metabolism
Transcriptome genetics
Bunyaviridae Infections metabolism
DNA, Mitochondrial metabolism
Inflammasomes metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Phlebovirus physiology
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 30
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 32234474
- Full Text :
- https://doi.org/10.1016/j.celrep.2020.02.105