Autophagy induced by taurolidine protects against polymicrobial sepsis by promoting both host resistance and disease tolerance.
Autophagy induced by taurolidine protects against polymicrobial sepsis by promoting both host resistance and disease tolerance.
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牛磺罗定诱导的自噬通过促进宿主抵抗力和耐受性来预防多种微生物败血症
DOI：
10.1073/pnas.2121244119
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发表时间：
2022-05-10
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
疾病抗性和耐受性是进化上保守但独特的防御策略，保护宿主免受微生物感染。在这里，我们报道在感染开始前施用牛罗列丁可通过促进耐药性和耐受性来保护多微生物败血症。值得注意的是，在感染发生后给予牛磺酸丁也可以通过增强疾病对器官损伤的耐受性来拯救败血症相关的致死率。这种保护依赖于完整的自噬途径，因为牛罗列丁不能保护自噬缺陷小鼠免受微生物败血症的侵害。具体来说，牛磺酸醚在巨噬细胞中诱导轻链3相关的吞噬作用，而不是异种吞噬，从而增强了细胞对感染的抵抗力，增强了杀菌活性。这些结果强调了自噬诱导对牛磺酸增强宿主的抗性和疾病耐受性以及随后的保护的重要性。脓毒症、脓毒性休克及其后遗症是重症监护病房死亡的主要原因，治疗选择有限。疾病抗性和耐受性是两种进化上保守但不同的防御策略，保护宿主免受微生物感染。在这里，我们报道，在脓毒症攻击前6小时给予牛罗列丁，通过促进宿主的抵抗力和疾病耐受性，以加速细菌清除，改善器官损伤，减少血管和肠道通透性为特征，对多微生物脓毒症具有很强的保护作用。值得注意的是，在脓毒症攻击后6小时给予牛罗列丁也可以通过增强对组织和器官损伤的疾病耐受性来拯救小鼠免于脓毒症相关的死亡。重要的是，牛罗列定提供的体内保护依赖于完整的自噬途径，因为牛罗列定保护野生型小鼠，但无法拯救微生物败血症的自噬缺陷小鼠。在体外实验中，牛磺酸醚诱导先天吞噬细胞轻链3相关的吞噬作用以及血管内皮和肠道上皮的自噬作用，增强了这些细胞的杀菌活性，增强了细胞对内毒素诱导损伤的耐受性。这些结果表明，牛磺酸醚诱导的自噬增强了宿主对细菌感染的抵抗力和疾病耐受性，从而赋予了对微生物败血症的保护。
Disease resistance and tolerance are evolutionarily conserved yet distinct defense strategies that protect the host against microbial infection. Here, we report that taurolidine administered before the start of infection confers protection against polymicrobial sepsis by promoting resistance and tolerance. Notably, taurolidine given after the onset of infection also rescues mice from sepsis-associated lethality by enhancing disease tolerance to organ damage. This protection relies on an intact autophagy pathway, as taurolidine fails to protect autophagy-deficient mice against microbial sepsis. Specifically, taurolidine induces light chain 3-associated phagocytosis, but not xenophagy, in macrophages, resulting in an augmented bactericidal activity with enhanced cellular resistance to infection. These results highlight the importance of autophagy induction for taurolidine-augmented host resistance and disease tolerance and subsequent protection. Sepsis, septic shock, and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Disease resistance and tolerance are two evolutionarily conserved yet distinct defense strategies that protect the host against microbial infection. Here, we report that taurolidine administered at 6 h before septic challenge led to strong protection against polymicrobial sepsis by promoting both host resistance and disease tolerance characterized by accelerated bacterial clearance, ameliorated organ damage, and diminished vascular and gut permeability. Notably, taurolidine administered at 6 h after septic challenge also rescued mice from sepsis-associated lethality by enhancing disease tolerance to tissue and organ injury. Importantly, this in vivo protection afforded by taurolidine depends on an intact autophagy pathway, as taurolidine protected wild-type mice but was unable to rescue autophagy-deficient mice from microbial sepsis. In vitro, taurolidine induced light chain 3-associated phagocytosis in innate phagocytes and autophagy in vascular endothelium and gut epithelium, resulting in augmented bactericidal activity and enhanced cellular tolerance to endotoxin-induced damage in these cells. These results illustrate that taurolidine-induced autophagy augments both host resistance and disease tolerance to bacterial infection, thereby conferring protection against microbial sepsis.
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影响因子：
3.3
作者：
Ayres, Janelle S.;Freitag, Nancy;Schneider, David S.
通讯作者：
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