Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials.
Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials.
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DOI：
10.1128/mbio.00023-21
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发表时间：
2021-03-30
期刊：
影响因子：
6.4
通讯作者：
Rupp J
中科院分区：
文献类型：
--
作者：
Shima K;Kaufhold I;Eder T;Käding N;Schmidt N;Ogunsulire IM;Deenen R;Köhrer K;Friedrich D;Isay SE;Grebien F;Klinger M;Richer BC;Günther UL;Deepe GS Jr;Rattei T;Rupp J
在真核细胞中，ATP的产生主要是由这种蛋白质所产生，它的活性被用来控制沙眼衣原体的细胞内生长。此外，线粒体活性与宿主脂肪酸的合成密切相关，而宿主脂肪酸的合成是衣原体膜生物合成所不可或缺的。专性细胞内细菌沙眼衣原体感染是世界范围内最常见的细菌性性传播疾病。由于目前还没有疫苗，抗菌治疗是唯一的选择。沙眼感染然而，衣原体复制活性的变化和衣原体持久性的发生所造成的不同的刺激已被证明损害治疗效果。在这里，我们报告的机制，C。沙眼衣原体调节宿主信号传导过程和线粒体功能，其可用于在用β-内酰胺抗菌剂治疗期间的衣原体代谢重编程。信号转导子和转录激活子3（STAT 3）的激活是各种细菌和病毒感染中众所周知的宿主应答。In C.在沙眼衣原体感染中，宿主蛋白酪氨酸磷酸酶对STAT 3的失活在β-内酰胺抗菌剂存在和不存在的情况下均增加线粒体呼吸。然而，在β-内酰胺类抗生素治疗期间，C.沙眼衣原体增加了柠檬酸的产生以及参与脂肪酸合成的宿主ATP-柠檬酸裂解酶的活性。同时，衣原体代谢从三羧酸循环转换为脂肪酸合成。这种代谢转换是β-内酰胺类抗生素治疗的独特反应，在γ干扰素（IFN-γ）诱导的持续感染中未观察到。抑制脂肪酸合成能够减弱β-内酰胺诱导的衣原体持续存在。我们的研究结果强调了脂肪酸-脂肪酸相互作用对C.β-内酰胺类抗生素治疗期间的沙眼。
The mitochondrion generates most of the ATP in eukaryotic cells, and its activity is used for controlling the intracellular growth of Chlamydia trachomatis. Furthermore, mitochondrial activity is tightly connected to host fatty acid synthesis that is indispensable for chlamydial membrane biogenesis. Infection with the obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide. Since no vaccine is available to date, antimicrobial therapy is the only alternative in C. trachomatis infection. However, changes in chlamydial replicative activity and the occurrence of chlamydial persistence caused by diverse stimuli have been proven to impair treatment effectiveness. Here, we report the mechanism for C. trachomatis regulating host signaling processes and mitochondrial function, which can be used for chlamydial metabolic reprogramming during treatment with β-lactam antimicrobials. Activation of signal transducer and activator of transcription 3 (STAT3) is a well-known host response in various bacterial and viral infections. In C. trachomatis infection, inactivation of STAT3 by host protein tyrosine phosphatases increased mitochondrial respiration in both the absence and presence of β-lactam antimicrobials. However, during treatment with β-lactam antimicrobials, C. trachomatis increased the production of citrate as well as the activity of host ATP-citrate lyase involved in fatty acid synthesis. Concomitantly, chlamydial metabolism switched from the tricarboxylic acid cycle to fatty acid synthesis. This metabolic switch was a unique response in treatment with β-lactam antimicrobials and was not observed in gamma interferon (IFN-γ)-induced persistent infection. Inhibition of fatty acid synthesis was able to attenuate β-lactam-induced chlamydial persistence. Our findings highlight the importance of the mitochondrion-fatty acid interplay for the metabolic reprogramming of C. trachomatis during treatment with β-lactam antimicrobials.