2. Academic Validation
  3. SFTSV Infection Induces BAK/BAX-Dependent Mitochondrial DNA Release to Trigger NLRP3 Inflammasome Activation

SFTSV Infection Induces BAK/BAX-Dependent Mitochondrial DNA Release to Trigger NLRP3 Inflammasome Activation

  • Cell Rep. 2020 Mar 31;30(13):4370-4385.e7. doi: 10.1016/j.celrep.2020.02.105.
Shufen Li 1,  Hao Li 2,  Yu-Lan Zhang 1,  Qi-Lin Xin 1,  Zhen-Qiong Guan 3,  Xi Chen 4,  Xiao-Ai Zhang 2,  Xiao-Kun Li 2,  Geng-Fu Xiao 1,  Pierre-Yves Lozach 5,  Jun Cui 6,  Wei Liu 7,  Lei-Ke Zhang 8,  Ke Peng 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, P. R. China.
  • 2 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing Key Laboratory of Vector Borne and Natural Focus Infectious Diseases, Beijing 100071, P. R. China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, P. R. China; University of the Chinese Academy of Sciences, Beijing 100049, P. R. China.
  • 4 Department of Thoracic and Vascular Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China.
  • 5 Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany; IVPC UMR754, INRA, University of Lyon, EPHE, 50 Av. Tony Garnier, 69007 Lyon, France.
  • 6 MOE Key Laboratory of Gene Function and Regulation, State Key Lab of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.
  • 7 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing Key Laboratory of Vector Borne and Natural Focus Infectious Diseases, Beijing 100071, P. R. China. Electronic address: liuwei@bmi.ac.cn.
  • 8 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, P. R. China; University of the Chinese Academy of Sciences, Beijing 100049, P. R. China. Electronic address: zhangleike@wh.iov.cn.
  • 9 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, P. R. China; University of the Chinese Academy of Sciences, Beijing 100049, P. R. China. Electronic address: pengke@wh.iov.cn.
PMID: 32234474 DOI: 10.1016/j.celrep.2020.02.105
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.

Keywords

BAK; BAX; NLRP3 inflammasome; SFTSV; mitochondrial DNA.

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