Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection.
Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection.
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DOI：
10.1016/j.chom.2022.03.028
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发表时间：
2022-07-13
影响因子：
30.3
通讯作者：
Woodward, Joshua J.
中科院分区：
文献类型：
--
作者：
Tang, Qing;Precit, Mimi R.;Thomason, Maureen K.;Blanc, Sophie F.;Ahmed-Qadri, Fariha;McFarland, Adelle P.;Wolter, Daniel J.;Hoffman, Lucas R.;Woodward, Joshua J.
抗菌剂可影响细菌生理学和宿主免疫力，导致不良治疗结果。广泛暴露于抗叶酸抗生素促进胸苷依赖性金黄色葡萄球菌小菌落变异（TD-SCV），通常与更差的临床结局相关。我们表明，胸腺嘧啶核苷合成的介导的破坏促进细菌第二信使环二AMP（c-di-AMP）的水平升高，从而诱导宿主STING激活和炎症。在厚壁菌门中的初始抗生素筛选显示，c-di-AMP生产主要由靶向二氢叶酸还原酶（DHFR）的抗叶酸抗生素驱动，所述二氢叶酸还原酶促进胸苷生物合成所需的叶酸再生。此外，TD-SCV表现出过度的c-di-AMP生产和STING激活的胸苷依赖性的方式。与正常集落S相比，用TD-SCV感染小鼠肺显示促炎细胞因子的STING依赖性升高，导致更高的气道中性粒细胞浸润和活化。金黄色葡萄球菌和氯化血红素依赖性SCV。总的来说，我们的研究结果表明，厚壁菌门中的胸苷代谢中断导致c-di-AMP介导的STING依赖性炎症升高，对抗生素使用和感染结果具有潜在影响。Tang等人发现，抗叶酸抗生素对胸苷生物合成的破坏诱导许多致病性厚壁菌门物种的c-di-AMP产生升高，从而导致更高的STING活化。这项研究揭示了抗生素治疗和宿主炎症之间的未被重视的联系。
Antimicrobials can impact bacterial physiology and host immunity with negative treatment outcomes. Extensive exposure to anti-folate antibiotics promotes thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), commonly associated with worse clinical outcomes. We show that antibiotic-mediated disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c-di-AMP), consequently inducing host STING activation and inflammation. An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by anti-folate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis. Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent manner. Murine lung infection with TD-SCVs revealed STING-dependent elevation of proinflammatory cytokines, causing higher airway neutrophil infiltration and activation compared to normal colony S. aureus and hemin-dependent SCVs. Collectively, our results suggest that thymidine metabolism disruption in Firmicutes leads to elevated c-di-AMP-mediated STING-dependent inflammation, with potential impacts on antibiotic usage and infection outcomes. Tang et al find that disruption of thymidine biosynthesis by anti-folate antibiotic induces elevated c-di-AMP production of many pathogenic Firmicutes species, which consequently leads to higher STING activation. This study reveals an unappreciated link between antibiotic therapy and host inflammation.
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影响因子：
9.4
作者：
Besier, Silke;Smaczny, Christina;Wichelhaus, Thomas A.
通讯作者：
Wichelhaus, Thomas A.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.3390/ph3051694
发表时间：
2010-05-25
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Anderson R;Tintinger G;Cockeran R;Potjo M;Feldman C
通讯作者：
Feldman C
影响因子：
5.8
作者：
Hawser, S;Lociuro, S;Islam, K
通讯作者：
Islam, K
影响因子：
4.9
作者：
Argudin, M. Angeles;Roisin, S.;Denis, O.
通讯作者：
Denis, O.