Staphylococcus aureus is a deadly pathogen that causes fatal diseases in humans. During infection, S. aureus secretes nuclease (Nuc) and adenosine synthase A (AdsA) to generate cytotoxic deoxyadenosine (dAdo) from neutrophil extracellular traps which triggers noninflammatory apoptosis in macrophages. In this manner, replicating staphylococci escape phagocytic killing without alerting the immune system. Here, we show that mice lacking caspase-3 in immune cells exhibit increased resistance toward S. aureus Caspase-3-deficient macrophages are resistant to staphylococcal dAdo and gain access to abscess lesions to promote bacterial clearance in infected animals. We identify specific single nucleotide polymorphisms in CASP3 as candidate human resistance alleles that protect macrophages from S. aureus-derived dAdo, raising the possibility that the allelic repertoire of caspase-3 may contribute to the outcome of S. aureus infections in humans.IMPORTANCE Caspase-3 controls the apoptotic pathway, a form of programmed cell death designed to be immunologically silent. Polymorphisms leading to reduced caspase-3 activity are associated with variable effects on tumorigenesis and yet arise frequently. Staphylococcus aureus is a human commensal and a frequent cause of soft tissue and bloodstream infections. Successful commensalism and virulence can be explained by the secretion of a plethora of immune evasion factors. One such factor, AdsA, destroys phagocytic cells by exploiting the apoptotic pathway. However, human CASP3 variants with loss-of-function alleles shield phagocytes from AdsA-mediated killing. This finding raises the possibility that some caspase-3 alleles may arise from exposure to S. aureus and other human pathogens that exploit the apoptotic pathway for infection.

中文翻译：

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金黄色葡萄球菌利用宿主细胞凋亡途径在感染过程中持续存在。

金黄色葡萄球菌是一种致命的病原体，可导致人类致命的疾病。在感染过程中，金黄色葡萄球菌分泌核酸酶（Nuc）和腺苷合酶A（AdsA），从嗜中性粒细胞胞外诱捕器产生细胞毒性脱氧腺苷（dAdo），从而触发巨噬细胞的非炎性细胞凋亡。以这种方式，复制的葡萄球菌可以逃避吞噬作用的杀死，而不会引起免疫系统的警觉。在这里，我们显示在免疫细胞中缺乏caspase-3的小鼠表现出对金黄色葡萄球菌的抗性增加。缺乏caspase-3的巨噬细胞对葡萄球菌dAdo具有抗性，并且可以进入脓肿病灶以促进感染动物的细菌清除。我们在CASP3中鉴定了特定的单核苷酸多态性作为候选的人类抗性等位基因，可以保护巨噬细胞免受金黄色葡萄球菌衍生的dAdo的侵害，caspase-3的等位基因库可能有助于人类金黄色葡萄球菌感染的结果。重要提示caspase-3控制凋亡途径，一种程序性细胞死亡，设计为免疫沉默。导致caspase-3活性降低的多态性与肿瘤发生的可变效应有关，但仍经常出现。金黄色葡萄球菌是人类的常见病，是软组织和血液感染的常见原因。成功的共鸣和毒力可以通过分泌大量免疫逃逸因子来解释。一种这样的因子AdsA通过利用凋亡途径破坏吞噬细胞。但是，具有功能丧失等位基因的人CASP3变体可保护吞噬细胞免受AdsA介导的杀伤。