Nikolka Fabian, Karagöz Mustafa Safa, Nassef Mohamed Zakaria, Hiller Karsten, Steinert Michael, Cordes Thekla
Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106 Braunschweig, Germany.
Institut für Mikrobiologie, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106 Braunschweig, Germany.
Metabolites. 2023 Jul 11;13(7):834. doi: 10.3390/metabo13070834.
() is a common etiological agent of bacterial pneumonia that causes Legionnaires' disease (LD). The bacterial membrane-associated virulence factor macrophage infectivity potentiator (Mip) exhibits peptidyl-prolyl--isomerase (PPIase) activity and contributes to the intra- and extracellular pathogenicity of . Though Mip influences disease outcome, little is known about the metabolic consequences of altered Mip activity during infections. Here, we established a metabolic workflow and applied mass spectrometry approaches to decipher how Mip activity influences metabolism and pathogenicity. Impaired Mip activity in genetically engineered strains decreases intracellular replication in cellular infection assays, confirming the contribution of Mip for pathogenicity. We observed that genetic and chemical alteration of Mip using the PPIase inhibitors rapamycin and FK506 induces metabolic reprogramming in , specifically branched-chain amino acid (BCAA) metabolism. Rapamycin also inhibits PPIase activity of mammalian FK506 binding proteins, and we observed that rapamycin induces a distinct metabolic signature in human macrophages compared to bacteria, suggesting potential involvement of Mip in normal bacteria and in infection. Our metabolic studies link Mip to alterations in BCAA metabolism and may help to decipher novel disease mechanisms associated with LD.
（某病原体）是引起军团病（LD）的细菌性肺炎的常见病原体。细菌膜相关毒力因子巨噬细胞感染增强因子（Mip）具有肽基脯氨酰异构酶（PPIase）活性，有助于该病原体在细胞内外的致病性。尽管Mip会影响疾病结局，但对于感染期间Mip活性改变的代谢后果知之甚少。在此，我们建立了一种代谢工作流程并应用质谱方法来解读Mip活性如何影响代谢和致病性。在细胞感染试验中，基因工程改造菌株中受损的Mip活性降低了细胞内复制，证实了Mip对该病原体致病性的作用。我们观察到，使用PPIase抑制剂雷帕霉素和FK506对Mip进行基因和化学改变会诱导该病原体发生代谢重编程，特别是支链氨基酸（BCAA）代谢。雷帕霉素还抑制哺乳动物FK506结合蛋白的PPIase活性，并且我们观察到，与细菌相比，雷帕霉素在人类巨噬细胞中诱导出不同的代谢特征，这表明Mip可能参与正常细菌及感染过程。我们的代谢研究将Mip与BCAA代谢改变联系起来，可能有助于解读与军团病相关的新疾病机制。
