Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis.
Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis.
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DOI：
10.1038/s41564-019-0597-0
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发表时间：
2020-01
影响因子：
28.3
通讯作者：
中科院分区：
文献类型：
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作者：
金黄色葡萄球菌小菌落变体 (SCV) 经常与慢性感染相关，但它们缺乏许多与野生型菌株致病性相关的毒力决定簇的表达。我们发现野生型金黄色葡萄球菌和 ΔhemB SCV 原型均可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坏死性凋亡，这是一种独立于半胱天冬酶的宿主细胞死亡机制，无法根除金黄色葡萄球菌，反而促进了 ΔhemB SCV 的致病性。为了支持正在进行的糖酵解活动，ΔhemB SCV 诱导 fumC 的表达增加超过 100 倍，fumC 编码一种催化富马酸（糖酵解抑制剂）降解的酶。与 fumC 依赖性的局部富马酸盐消耗一致，ΔhemB SCV 未能激发训练有素的免疫力和保护皮肤免受二次感染的挑战。金黄色葡萄球菌 SCV 群体对糖酵解的依赖在很大程度上解释了其在金黄色葡萄球菌皮肤感染发病机制中的作用。
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.
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影响因子：
6.4
作者：
Kobayashi, Scott D.;Malachowa, Natalia;DeLeo, Frank R.
通讯作者：
DeLeo, Frank R.
影响因子：
2.4
作者：
Barker, M;Rayens, W
通讯作者：
Rayens, W
影响因子：
6.7
作者：
González-Juarbe N;Gilley RP;Hinojosa CA;Bradley KM;Kamei A;Gao G;Dube PH;Bergman MA;Orihuela CJ
通讯作者：
Orihuela CJ
DOI：
10.1126/science.aan4665
发表时间：
2018-04-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kornberg MD;Bhargava P;Kim PM;Putluri V;Snowman AM;Putluri N;Calabresi PA;Snyder SH
通讯作者：
Snyder SH
影响因子：
11.8
作者：
Goodall ML;Fitzwalter BE;Zahedi S;Wu M;Rodriguez D;Mulcahy-Levy JM;Green DR;Morgan M;Cramer SD;Thorburn A
通讯作者：
Thorburn A