Dissecting the Transcriptomes of Multiple Metronidazole-Resistant and Sensitive <i>Trichomonas vaginalis</i> Strains Identified Distinct Genes and Pathways Associated with Drug Resistance and Cell Death
Po-Jung Huang,
Ching-Yun Huang,
Yu-Xuan Li,
Yi-Chung Liu,
Lichieh-Julie Chu,
Yuan-Ming Yeh,
Wei-Hung Cheng,
Ruei-Ming Chen,
Chi-Ching Lee,
Lih-Chyang Chen,
Hsin-Chung Lin,
Shu-Fang Chiu,
Wei-Ning Lin,
Ping-Chiang Lyu,
Petrus Tang,
Kuo-Yang Huang
Affiliations
Po-Jung Huang
Department of Biomedical Sciences, Chang Gung University, Taoyuan City 333, Taiwan
Ching-Yun Huang
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan
Yu-Xuan Li
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan
Yi-Chung Liu
Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu 300, Taiwan
Lichieh-Julie Chu
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan
Yuan-Ming Yeh
Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan
Wei-Hung Cheng
Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung City 824, Taiwan
Ruei-Ming Chen
Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
Chi-Ching Lee
Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan
Lih-Chyang Chen
Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan
Hsin-Chung Lin
Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
Shu-Fang Chiu
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan
Wei-Ning Lin
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan
Ping-Chiang Lyu
Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu 300, Taiwan
Petrus Tang
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan
Kuo-Yang Huang
Host-Parasite Interactions Laboratory, National Defense Medical Center, Taipei City 114, Taiwan
Trichomonas vaginalis is the causative agent of trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. Metronidazole (MTZ) is the mainstay of anti-trichomonal chemotherapy; however, drug resistance has become an increasingly worrying issue. Additionally, the molecular events of MTZ-induced cell death in T. vaginalis remain elusive. To gain insight into the differential expression of genes related to MTZ resistance and cell death, we conducted RNA-sequencing of three paired MTZ-resistant (MTZ-R) and MTZ-sensitive (MTZ-S) T. vaginalis strains treated with or without MTZ. Comparative transcriptomes analysis identified that several putative drug-resistant genes were exclusively upregulated in different MTZ-R strains, such as ATP-binding cassette (ABC) transporters and multidrug resistance pumps. Additionally, several shared upregulated genes among all the MTZ-R transcriptomes were not previously identified in T. vaginalis, such as 5′-nucleotidase surE and Na+-driven multidrug efflux pump, which are a potential stress response protein and a multidrug and toxic compound extrusion (MATE)-like protein, respectively. Functional enrichment analysis revealed that purine and pyrimidine metabolisms were suppressed in MTZ-S parasites upon drug treatment, whereas the endoplasmic reticulum-associated degradation (ERAD) pathway, proteasome, and ubiquitin-mediated proteolysis were strikingly activated, highlighting the novel pathways responsible for drug-induced stress. Our work presents the most detailed analysis of the transcriptional changes and the regulatory networks associated with MTZ resistance and MTZ-induced signaling, providing insights into MTZ resistance and cell death mechanisms in trichomonads.
