Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.

Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme
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Abstract

Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.

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酮体生成促进对铜绿假单胞菌肺部感染的耐受性。
铜绿假单胞菌是肺部感染的常见原因。作为革兰氏阴性病原体,它可以引发活跃且极具破坏性的炎症反应;然而,大多数宿主对细菌负荷具有耐受性,发展为慢性感染。使用小鼠肺炎模型,我们证明了生酮促进了从炎症到疾病耐受的转变。作为对肺部感染的反应,酮体在肝脏中产生并循环到肺部,在那里它们对不能显示表面脂多糖(LPS)的铜绿假单胞菌菌株进行选择。这种酮适应的LPS菌株不能激活糖酵解和破坏组织的细胞因子,反而促进脂肪的线粒体分解代谢和氧化磷酸化(OXPHOS),从而维持气道稳态。在肺部,铜绿假单胞菌利用宿主免疫代谢产物衣康酸盐进一步刺激生酮。此环境启用host-P。铜绿假单胞菌共存,支持细菌的病理适应性变化和通过OXPHOS维持呼吸完整性。
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