Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide.,Nature Microbiology

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Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide.
Nature Microbiology ( IF 20.5 ) Pub Date : 2019-12-23 , DOI: 10.1038/s41564-019-0620-5
Saskia D Günther ₁ , Melanie Fritsch ₁ , Jens M Seeger ₁ , Lars M Schiffmann _{1,

2} , Scott J Snipas ₃ , Maria Coutelle ₁ , Thomas A Kufer ₄ , Paul G Higgins ₅ , Veit Hornung ₆ , Maria L Bernardini ₇ , Stefan Höning ₈ , Martin Krönke ₁ , Guy S Salvesen ₃ , Hamid Kashkar ₁

Affiliation

The cytosolic appearance and propagation of bacteria cause overwhelming cellular stress responses that induce apoptosis under normal conditions. Therefore, successful bacterial colonization depends on the ability of intracellular pathogens to block apoptosis and to safeguard bacterial replicative niches. Here, we show that the cytosolic Gram-negative bacterium Shigella flexneri stalls apoptosis by inhibiting effector caspase activity. Our data identified lipopolysaccharide (LPS) as a bona fide effector caspase inhibitor that directly binds caspases by involving its O-antigen (O Ag) moiety. Bacterial strains that lacked the O Ag or failed to replicate within the cytosol were incapable of blocking apoptosis and exhibited reduced virulence in a murine model of bacterial infection. Our findings demonstrate how Shigella inhibits pro-apoptotic caspase activity, effectively delays coordinated host-cell demise and supports its intracellular propagation. Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points.

中文翻译：

胞质革兰氏阴性菌通过脂多糖抑制效应半胱天冬酶来防止细胞凋亡。

细菌的胞质外观和繁殖会导致压倒性的细胞应激反应，在正常条件下诱导细胞凋亡。因此，成功的细菌定植取决于细胞内病原体阻止细胞凋亡和保护细菌复制生态位的能力。在这里，我们显示细胞溶质革兰氏阴性细菌福氏志贺氏菌通过抑制效应半胱天冬酶活性来阻止细胞凋亡。我们的数据将脂多糖 (LPS) 鉴定为真正的效应半胱天冬酶抑制剂，它通过涉及其 O 抗原 (O Ag) 部分直接结合半胱天冬酶。缺乏 O Ag 或未能在胞质溶胶中复制的细菌菌株无法阻止细胞凋亡，并且在小鼠细菌感染模型中表现出毒力降低。我们的研究结果表明志贺氏菌如何抑制促凋亡半胱天冬酶活性，有效延迟协调的宿主细胞死亡并支持其细胞内传播。除了最近发现的细胞溶质 LPS 的促炎作用外，我们的数据还揭示了一种独特的 LPS 作用模式，通过破坏早期协调的非溶解性细胞死亡反应，最终支持感染细胞在后期时间点的炎症分解.

更新日期：2019-12-23

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