Dissecting the transcriptomes of multiple metronidazole-resistant and sensitive trichomonas vaginalis 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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number1817
JournalBiomedicines
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

Keywords

  • ABC transporter
  • Drug resistance
  • ERAD
  • Trichomoniasis

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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