Infectious Disease Control Science, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
Molecular Virology, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
PLoS Pathog. 2021 Oct 14;17(10):e1009841. doi: 10.1371/journal.ppat.1009841. eCollection 2021 Oct.
In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.
一般来说，在哺乳动物细胞中，细胞质 DNA 病毒被环鸟苷酸-腺苷酸合酶（cGAS）感知，而 RNA 病毒被视黄酸诱导基因 I（RIG-I）样受体识别，从而在宿主中触发一系列下游先天抗病毒信号步骤。我们之前报道过，具有 RNA 基因组的麻疹病毒（MeV）会诱导快速的抗病毒反应，随后在上皮细胞中全面下调宿主基因表达。有趣的是，基因本体分析表明，编码线粒体蛋白的基因在下调基因列表中富集。为了评估 MeV 感染后的线粒体应激，我们首先观察了感染细胞的线粒体形态，发现形成了具有超融合表型的显著拉长的线粒体网络。此外，在感染过程中细胞质中检测到线粒体 DNA（mtDNA）的增加。基于这些结果，我们表明在 MeV 感染过程中从超融合线粒体释放的细胞质 mtDNA 被 cGAS 捕获，并除了经典的 RNA 感应之外还引起 DNA 感应途径的初始。我们还确定了 cGAS 对 MeV 体内致病性的贡献。此外，我们发现其他引起与 MeV 相似的线粒体过度融合和细胞质 mtDNA-引发抗病毒反应的下调线粒体生物发生的病毒也会引起类似的反应。这些发现表明，mtDNA 激活的 cGAS 途径对于某些病毒的完全先天控制至关重要，包括导致线粒体应激的 RNA 病毒。
