title: Novel insights into the molecular events linking to cell death induced by tetracycline in the amitochondriate protozoan Trichomonas vaginalis.
abstract: Trichomonas vaginalis colonizes the human urogenital tract and causes trichomoniasis, the most common nonviral sexually transmitted disease. Currently, 5-nitroimidazoles are the only recommended drugs for treating trichomoniasis. However, increased resistance of the parasite to 5-nitroimidazoles has emerged as a highly problematic public health issue. Hence, it is essential to identify alternative chemotherapeutic agents against refractory trichomoniasis. Tetracycline (TET) is a broad-spectrum antibiotic with activity against several protozoan parasites, but the mode of action of TET in parasites remains poorly understood. The in vitro effect of TET on the growth of T. vaginalis was examined, and the mode of cell death was verified by various apoptosis-related assays. Next-generation sequencing-based RNA sequencing (RNA-seq) was employed to elucidate the transcriptome of T. vaginalis in response to TET. We show that TET has a cytotoxic effect on both metronidazole (MTZ)-sensitive and -resistant T. vaginalis isolates, inducing some features resembling apoptosis. RNA-seq data reveal that TET significantly alters the transcriptome via activation of specific pathways, such as aminoacyl-tRNA synthetases and carbohydrate metabolism. Functional analyses demonstrate that TET disrupts the hydrogenosomal membrane potential and antioxidant system, which concomitantly elicits a metabolic shift toward glycolysis, suggesting that the hydrogenosomal function is impaired and triggers cell death. Collectively, we provide in vitro evidence that TET is a potential alternative therapeutic choice for treating MTZ-resistant T. vaginalis. The in-depth transcriptomic signatures in T. vaginalis upon TET treatment presented here will shed light on the signaling pathways linking to cell death in amitochondriate organisms.
authors: Molecular Regulation and Bioinformatics Laboratory, Department of Parasitology, Chang Gung University, Taoyuan, Taiwan Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors: Kuo-Yang
authors: KY
authors: Huang
authors: Molecular Regulation and Bioinformatics Laboratory, Department of Parasitology, Chang Gung University, Taoyuan, Taiwan.
authors: Fu-Man
authors: FM
authors: Ku
authors: Molecular Regulation and Bioinformatics Laboratory, Department of Parasitology, Chang Gung University, Taoyuan, Taiwan Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors: Wei-Hung
authors: WH
authors: Cheng
authors: Bioinformatics Center, Chang Gung University, Taoyuan, Taiwan.
authors: Chi-Ching
authors: CC
authors: Lee
authors: Bioinformatics Center, Chang Gung University, Taoyuan, Taiwan.
authors: Po-Jung
authors: PJ
authors: Huang
authors: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors: Lichieh Julie
authors: LJ
authors: Chu
authors: Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors: Chih-Chieh
authors: CC
authors: Cheng
authors: Molecular Regulation and Bioinformatics Laboratory, Department of Parasitology, Chang Gung University, Taoyuan, Taiwan Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors: Yi-Kai
authors: YK
authors: Fang
authors: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
authors: Hsueh-Hsia
authors: HH
authors: Wu
authors: Molecular Regulation and Bioinformatics Laboratory, Department of Parasitology, Chang Gung University, Taoyuan, Taiwan Bioinformatics Center, Chang Gung University, Taoyuan, Taiwan Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan petang@mail.cgu.edu.tw.
authors: Petrus
authors: P
authors: Tang
mesh_terms: D000994:Antitrichomonal Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D013752:Tetracycline / Q000494:pharmacology*; D014246:Trichomonas vaginalis / Q000187:drug effects*
chemical_list: D000994:Antitrichomonal Agents; D013752:Tetracycline