Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease in the tropics and subtropics with high morbidity and mortality. The facultative intracellular bacterium induces host cell fusion through its type VI secretion system 5 (T6SS5) as an important part of its pathogenesis in mammalian hosts. This allows it to spread intercellularly without encountering extracellular host defenses. We report that bacterial T6SS5-dependent cell fusion triggers type I IFN gene expression in the host and leads to activation of the cGAMP synthase–stimulator of IFN genes (cGAS–STING) pathway, independent of bacterial ligands. Aberrant and abortive mitotic events result in the formation of micronuclei colocalizing with cGAS, which is activated by double-stranded DNA. Surprisingly, cGAS–STING activation leads to type I IFN transcription but not its production. Instead, the activation of cGAS and STING results in autophagic cell death. We also observed type I IFN gene expression, micronuclei formation, and death of chemically induced cell fusions. Therefore, we propose that the cGAS–STING pathway senses unnatural cell fusion through micronuclei formation as a danger signal, and consequently limits aberrant cell division and potential cellular transformation through autophagic death induction.

假伯克霍尔德氏菌是类鼻疽病的病原体，后者是热带和亚热带地区的一种传染病，发病率和死亡率很高。兼性细胞内细菌通过其VI型分泌系统5（T6SS5）诱导宿主细胞融合，这是其在哺乳动物宿主中发病机理的重要组成部分。这使其可以在细胞间扩散而不会遇到细胞外宿主防御。我们报道细菌T6SS5依赖性细胞融合触发宿主中的I型IFN基因表达，并导致cGAMP合酶-IFN基因刺激物（cGAS-STING）途径的激活，而与细菌配体无关。异常和流产的有丝分裂事件导致与cGAS共定位的微核的形成，其被双链DNA激活。出乎意料的是，cGAS–STING激活导致I型IFN转录，但没有产生。相反，cGAS和STING的激活导致自噬细胞死亡。我们还观察到I型IFN基因表达，微核形成和化学诱导细胞融合的死亡。因此，我们建议cGAS–STING途径通过微核形成将不自然的细胞融合感知为危险信号，并因此通过自噬死亡诱导限制异常的细胞分裂和潜在的细胞转化。