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
复制标题
SFTSV 感染诱导 BAK/BAX 依赖性线粒体 DNA 释放以触发 NLRP3 炎症小体激活
DOI：
10.1016/j.celrep.2020.02.105
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发表时间：
2020-03-31
期刊：
影响因子：
8.8
通讯作者：
Peng, Ke
中科院分区：
文献类型：
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作者：
Li, Shufen;Li, Hao;Peng, Ke
严重发热伴血小板减少综合征 (SFTS) 病毒 (SFTSV) 是一种新兴的蜱传病毒，死亡率高达 12%-50%。深入了解 SFTSV 诱导的发病机制对于开发有效的抗 SFTS 疗法至关重要。在这里，我们报告了 SFTS 患者血液样本的转录组分析。我们观察到炎症反应与疾病进展和致命结果之间存在很强的相关性。 SFTSV 感染的定量蛋白质组学分析证实了炎症的诱导，并进一步揭示了病毒诱导的线粒体功能障碍。从机制上讲，SFTSV 感染触发 BCL2 拮抗剂/杀伤剂 1 (BAK) 上调和 BAK/BCL2 相关 X (BAX) 激活，导致线粒体 DNA (mtDNA) 氧化和随后的胞质释放。胞质 mtDNA 结合并触发 NLRP3 炎性体激活。值得注意的是，BAK 表达水平与 SFTS 疾病进展和致命结果相关。这些发现为了解严重 SFTS 的临床特征和分子基础提供了见解，这可能有助于患者护理和治疗设计，并且在其他高致病性病毒感染期间也可能得到保留。
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.