School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA, 99164, USA.
Paul G. Allen School for Global Health, College of Veterinary Medicine, Washington State University, Pullman, WA, 99164, USA.
Cell Death Dis. 2024 Mar 8;15(3):195. doi: 10.1038/s41419-024-06573-1.
STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii is a Gram-negative obligate intracellular bacterium and the causative agent of the zoonotic disease Q fever. The ability of C. burnetii to inhibit host cell death is a critical factor in disease development. Previous studies have shown that C. burnetii inhibits host cell apoptosis at early stages of infection. However, during the late-stages of infection, there is host cell lysis resulting in the release of bacteria to infect bystander cells. Thus, we investigated the role of STING during late-stages of C. burnetii infection and examined STING's impact on host cell death. We show that the loss of STING results in higher bacterial loads and abrogates IFNβ and IL6 induction at 12 days post-infection. The absence of STING during C. burnetii infection significantly reduces apoptosis through decreased caspase-8 and -3 activation. During infection, STING activates IRF3 which interacts with BAX. BAX then translocates to the mitochondria, which is followed by mitochondrial membrane depolarization. This results in increased cytosolic mtDNA in a STING-dependent manner. The presence of increased cytosolic mtDNA results in greater cytosolic 2'-3' cGAMP, creating a positive feedback loop and leading to further increases in STING activation and its downstream signaling. Taken together, we show that STING signaling is critical for BAX-IRF3-mediated mitochondria-induced apoptosis during late-stage C. burnetii infection.
STING（干扰素基因刺激物）是一种细胞溶质传感器，可在与 CDNs 结合后引发先天免疫反应。柯克斯体是一种革兰氏阴性专性细胞内细菌，也是人畜共患疾病 Q 热的病原体。C. burnetii 抑制宿主细胞死亡的能力是疾病发展的关键因素。先前的研究表明，C. burnetii 在感染早期抑制宿主细胞凋亡。然而，在感染后期，宿主细胞裂解导致细菌释放并感染旁观者细胞。因此，我们研究了 STING 在 C. burnetii 感染后期的作用，并检查了 STING 对宿主细胞死亡的影响。我们发现，STING 的缺失会导致细菌载量增加，并在感染后 12 天消除 IFNβ 和 IL6 的诱导。在 C. burnetii 感染期间缺乏 STING 会通过降低半胱天冬酶-8 和 -3 的激活来显著减少细胞凋亡。在感染过程中，STING 激活 IRF3，IRF3 与 BAX 相互作用。BAX 随后易位到线粒体，随后线粒体膜去极化。这导致以 STING 依赖的方式增加细胞溶质中的 mtDNA。增加的细胞溶质 mtDNA 导致更多的细胞溶质 2'-3' cGAMP，形成正反馈回路，导致 STING 激活及其下游信号进一步增加。总之，我们表明，STING 信号对于 BAX-IRF3 介导的晚期 C. burnetii 感染期间线粒体诱导的细胞凋亡至关重要。
