Research Group Pathogenesis of Bacterial Infections; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
PLoS Pathog. 2023 Dec 29;19(12):e1011892. doi: 10.1371/journal.ppat.1011892. eCollection 2023 Dec.
Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of death-effector deoxyribonucleosides, which kill infectious foci-penetrating macrophages. However, the exact mechanisms whereby staphylococcal death-effector deoxyribonucleosides and coupled imbalances of intracellular deoxyribonucleotide species provoke immune cell death remain elusive. Here, we report that S. aureus systematically promotes an overload of deoxyribonucleotides to trigger mitochondrial rupture in macrophages, a fatal event that induces assembly of the caspase-9-processing apoptosome and subsequent activation of the intrinsic pathway of apoptosis. Remarkably, genetic disruption of this cascade not only helps macrophages coping with death-effector deoxyribonucleoside-mediated cytotoxicity but also enhances their infiltration into abscesses thereby ameliorating pathogen control and infectious disease outcomes in laboratory animals. Combined with the discovery of protective alleles in human CASP9, these data highlight the role of mitochondria-centered apoptosis during S. aureus infection and suggest that gene polymorphisms may shape human susceptibility toward a predominant pathogen.
金黄色葡萄球菌是一种危险的病原体，它进化出了精细的免疫逃避策略来对抗宿主的免疫反应。这涉及到致死效应脱氧核苷酸的生物发生，它可以杀死感染灶穿透的巨噬细胞。然而，金黄色葡萄球菌致死效应脱氧核苷酸的精确机制以及细胞内脱氧核苷酸种类的失衡如何引发免疫细胞死亡仍然难以捉摸。在这里，我们报告金黄色葡萄球菌系统地促进脱氧核苷酸过载，以在巨噬细胞中引发线粒体破裂，这是一个致命事件，会诱导半胱天冬酶-9 加工凋亡小体的组装，并随后激活细胞凋亡的内在途径。值得注意的是，该级联反应的遗传中断不仅有助于巨噬细胞应对致死效应脱氧核苷酸介导的细胞毒性，还增强了它们向脓肿的浸润，从而改善了实验动物中病原体的控制和传染病的结果。结合人类 CASP9 中的保护性等位基因的发现，这些数据强调了线粒体中心细胞凋亡在金黄色葡萄球菌感染过程中的作用，并表明基因多态性可能影响人类对主要病原体的易感性。
