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Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis.
Nature Microbiology ( IF 20.5 ) Pub Date : 2019-11-04 , DOI: 10.1038/s41564-019-0597-0 Tania Wong Fok Lung 1 , Ian R Monk 2 , Karen P Acker 1 , Andre Mu 2, 3 , Nancy Wang 2 , Sebastián A Riquelme 1 , Silvia Pires 1 , Loreani P Noguera 1 , Felix Dach 1 , Stanislaw J Gabryszewski 1 , Benjamin P Howden 2, 3, 4 , Alice Prince 1
Nature Microbiology ( IF 20.5 ) Pub Date : 2019-11-04 , DOI: 10.1038/s41564-019-0597-0 Tania Wong Fok Lung 1 , Ian R Monk 2 , Karen P Acker 1 , Andre Mu 2, 3 , Nancy Wang 2 , Sebastián A Riquelme 1 , Silvia Pires 1 , Loreani P Noguera 1 , Felix Dach 1 , Stanislaw J Gabryszewski 1 , Benjamin P Howden 2, 3, 4 , Alice Prince 1
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Staphylococcus aureus small colony variants (SCVs) are frequently associated with chronic infection, yet they lack expression of many virulence determinants associated with the pathogenicity of wild-type strains. We found that both wild-type S. aureus and a ΔhemB SCV prototype potently activate glycolysis in host cells. Glycolysis and the generation of mitochondrial reactive oxygen species were sufficient to induce necroptosis, a caspase-independent mechanism of host cell death that failed to eradicate S. aureus and instead promoted ΔhemB SCV pathogenicity. To support ongoing glycolytic activity, the ΔhemB SCV induced over a 100-fold increase in the expression of fumC, which encodes an enzyme that catalyses the degradatin of fumarate, an inhibitor of glycolysis. Consistent with fumC-dependent depletion of local fumarate, the ΔhemB SCV failed to elicit trained immunity and protection from a secondary infectious challenge in the skin. The reliance of the S. aureus SCV population on glycolysis accounts for much of its role in the pathogenesis of S. aureus skin infection.
中文翻译：
金黄色葡萄球菌小菌落变体通过激活宿主细胞糖酵解和诱导坏死性凋亡来损害宿主免疫力。
金黄色葡萄球菌小菌落变异体 (SCV) 通常与慢性感染有关，但它们缺乏与野生型菌株致病性相关的许多毒力决定因子的表达。我们发现野生型金黄色葡萄球菌和 ΔhemB SCV 原型都能有效激活宿主细胞中的糖酵解。糖酵解和线粒体活性氧的产生足以诱导细胞坏死，这是宿主细胞死亡的半胱天冬酶非依赖性机制，未能根除金黄色葡萄球菌，反而促进了 ΔhemB SCV 致病性。为了支持持续的糖酵解活动，ΔhemB SCV 诱导 fumC 表达增加 100 倍以上，fumC 编码一种酶，该酶催化糖酵解抑制剂富马酸盐的降解。与局部富马酸盐的 fumC 依赖性消耗一致，ΔhemB SCV 未能引发训练有素的免疫力和保护免受皮肤中的二次感染挑战。金黄色葡萄球菌 SCV 群体对糖酵解的依赖解释了它在金黄色葡萄球菌皮肤感染发病机制中的大部分作用。
更新日期：2019-11-04
中文翻译：
金黄色葡萄球菌小菌落变体通过激活宿主细胞糖酵解和诱导坏死性凋亡来损害宿主免疫力。
金黄色葡萄球菌小菌落变异体 (SCV) 通常与慢性感染有关，但它们缺乏与野生型菌株致病性相关的许多毒力决定因子的表达。我们发现野生型金黄色葡萄球菌和 ΔhemB SCV 原型都能有效激活宿主细胞中的糖酵解。糖酵解和线粒体活性氧的产生足以诱导细胞坏死，这是宿主细胞死亡的半胱天冬酶非依赖性机制，未能根除金黄色葡萄球菌，反而促进了 ΔhemB SCV 致病性。为了支持持续的糖酵解活动，ΔhemB SCV 诱导 fumC 表达增加 100 倍以上，fumC 编码一种酶，该酶催化糖酵解抑制剂富马酸盐的降解。与局部富马酸盐的 fumC 依赖性消耗一致，ΔhemB SCV 未能引发训练有素的免疫力和保护免受皮肤中的二次感染挑战。金黄色葡萄球菌 SCV 群体对糖酵解的依赖解释了它在金黄色葡萄球菌皮肤感染发病机制中的大部分作用。
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