Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Germany.
Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
Nat Commun. 2024 Sep 11;15(1):7939. doi: 10.1038/s41467-024-52118-7.
Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells.
鲍曼不动杆菌是一种具有致病性和多重耐药性的革兰氏阴性菌，可引起严重的医院获得性感染。为了更好地了解发病机制，我们比较了未感染和感染的人细胞的蛋白质组，结果显示转录因子 FOS 是鲍曼不动杆菌感染后宿主蛋白中被诱导表达最强的蛋白。FOS 的药理学抑制可降低基于细胞的模型中鲍曼不动杆菌的细胞毒性，在小鼠感染模型中也观察到了类似的结果。研究表明，鲍曼不动杆菌外膜囊泡（OMVs）通过诱导宿主酶色氨酸-2,3-双加氧酶（TDO），产生配体犬尿氨酸，从而激活宿主细胞的芳烃受体（AHR），进而激活宿主细胞的 AHR。配体结合后，AHR 是 FOS 基因的直接转录激活因子。我们提出，鲍曼不动杆菌感染会影响宿主色氨酸代谢，并促进 AHR 和 FOS 介导的感染细胞的细胞毒性。
