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研究生:林信仲
研究生(外文):LIN, HSIN-CHUNG
論文名稱:抗甲硝唑陰道鞭毛蟲和精神疾病的相關性及其潛在抗藥機制
論文名稱(外文):The association between metronidazole-resistant Trichomonas vaginalis and psychiatric disorders and the potential mechanism of metronidazole-resistance
指導教授:闕宗熙闕宗熙引用關係
指導教授(外文):Chiueh, Tzong-Shi
口試委員:闕宗熙盧章智顏經洲簡戊鑑李忠信
口試委員(外文):CHIUEH, TZONG-SHILU, JANG-JIHYAN, JING-JOUChien,Wu-ChienLEE, CHUNG-SHINN
口試日期:2019-05-08
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:88
中文關鍵詞:陰道鞭毛蟲忽視的熱帶疾病精神疾病甲硝唑抗藥性蛋白質體學
外文關鍵詞:Trichomonas vaginalisNeglected tropical diseasesPsychiatric disordersMetronidazole resistanceProteome
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陰道鞭毛蟲症是最常見的非病毒的性傳染疾病。由於我們觀察到三軍總醫院裡有些陰道鞭毛蟲症病患者合併精神疾病,因此,我們利用台灣國民健康保險計劃的資料庫去研究陰道鞭毛蟲症與精神疾病的關聯性。
我們的結果顯示,追蹤十四年後,在陰道鞭毛蟲症組中,有875人(9.34%)患有精神疾病,而非陰道鞭毛蟲症組有1,988人(5.30%)(P <0.001)患有精神疾病。陰道鞭毛蟲症患者比非陰道鞭毛蟲症者多出1.644倍得到精神疾病。此外,45-64歲或低月保險費的陰道鞭毛蟲症患者更容易患精神疾病。更具體地說,陰道鞭毛蟲症患者發展成憂鬱症,焦慮症,雙相情感障礙,思覺失調症和藥物濫用的風險更高
甲硝唑是最常用於治療陰道鞭毛蟲症的藥物。我們的研究顯示陰道鞭毛蟲症患者接受甲硝唑有效治療,與降低發生憂鬱症、雙相情感障礙及思覺失調症的機率,具有相關性。此外,不管是第一次未使用藥物治療或是對甲硝唑有抗藥性,難治性陰道鞭毛蟲症(陰道鞭毛蟲症門診次數≥2)患者族群,發生精神疾病的風險較高,而且甲硝唑抗藥性蟲株,目前也是個高度討論的公共衛生議題。因此,我們想要使用蛋白質體學方法,去初步篩查陰道鞭毛蟲之甲硝唑抗藥性的可能分子機制標的。
我們發現,相較於甲硝唑敏感蟲株,甲硝唑抗藥蟲株的蛋白質組中,有304個差異表現蛋白(iTRAQ比率> 2或<0.5),包括228個上調蛋白和76個下調蛋白。而基因富集分析顯示胺基酸相關代謝,包括精氨酸,脯氨酸,丙氨酸,天冬氨酸和谷氨酸是甲硝唑抗藥株分離株中最上調的路徑,而氧化磷酸化是最下調的路徑。這表示藥物治療後,甲硝唑抗藥株寄生蟲的代謝重編程。值得注意的是,許多分類為氧化磷酸化基因的蛋白質都是三磷酸腺苷合成酶亞基之相關蛋白。我們也以實驗證明此篩查結果,在添加三磷酸腺苷合成酶抑制劑(寡黴素和巴弗洛黴素A1) 後,可增強甲硝唑敏感蟲株對甲硝唑的抗藥性。
總之,陰道鞭毛蟲特別是具備甲硝唑抗藥性的蟲株造成之頑固感染,在發展成精神疾病中可能扮演的角色,值得後續深入探討。另外,除了三磷酸腺苷合成酶亞基相關蛋白,經由蛋白質體篩查比對出的其他標的,將可作為研發與甲硝唑合併治療抗藥性蟲株的策略。
Trichomonas vaginalis (T. vaginalis) infection (trichomoniasis) is the most common non-viral sexually transmitted disease. We found that certain proportion of patients with trichomoniasis frequently visited the psychiatric department of Tri-Service General Hospital. Thus, we utilized the database of the National Health Insurance (NHI) program in Taiwan to investigate the association between trichomoniasis and psychiatric disorders.
Our results demonstrated that patients with trichomoniasis, 875 (9.34%) developed psychiatric disorders while only 1,988 (5.30%) in the non-trichomoniasis group (p < 0.001) during the 14 years of follow-up. The patients with trichomoniasis had 1.644 folds higher risk to develop psychiatric disorders. In addition, higher risk of mental disorders was observed in trichomoniasis patients of age around 45-64 and patients of lower monthly insured premium. More specifically, the study subjects had a higher risk for developing depression, anxiety, bipolar disorder, schizophrenia, and substance abuse.
Metronidazole (MTZ) is the most common drug for treating trichomoniasis. Our study revealed that effective MTZ treatment for trichomoniasis was significantly related with reducing the risk of depression, bipolar disorder and schizophrenia. Patients with possible refractory trichomoniasis (≥ 2 OPD visits for trichomoniasis) due to inappropriate treatment or drug resistance, had even higher rate of psychiatric disorders. Furthermore, MTZ-resistant T. vaginalis emerged and became a public health issue recently. Thus, we would like to unveil the molecular mechanisms of MTZ resistance in T. vaginalis using a comprehensive proteomic approach.
We found that 304 differentially expressed proteins in the MTZ-resistant (MTZ-R) proteome (iTRAQ ratio >2 or <0.5) compared to MTZ-sensitive (MTZ-S), including 228 upregulated and 76 downregulated proteins. Gene set enrichment analysis (GSEA) showed that the amino acid-related metabolism, including arginine, proline, alanine, aspartate, and glutamate are the most upregulated pathway in the MTZ-R isolate, whereas oxidative phosphorylation is the most downregulated pathway, suggesting a metabolic reprogramming in MTZ-R parasites following drug treatment. It is noteworthy that many proteins categorized into the gene set of oxidative phosphorylation were ATP synthase subunit-related proteins. The observation was also experimentally demonstrated by enhancing the MTZ-S parasites’ resistance to MTZ with addition of ATP synthase inhibitors, oligomycin or bafilomycin A1.
In summary, T. vaginalis, especially MTZ-R T. vaginalis, plays the novel role of developing psychiatric disorders in the future studies. Besides the ATP synthase subunit-related proteins, further elucidating the roles of other target proteins in resulting MTZ resistance of T. vaginalis would be beneficial for expanding the strategy for anti-parasite treatment.


Chapter 1. Introduction
1.1 Epidemiology of Trichomonas vaginalis
1.2 Pathogenesis
1.3 Microenvironments in the vagina
1.4 Clinical manifestations of trichomoniasis
1.5 Diagnosis of Trichomonas vaginalis
1.6 Trichomonas vaginalis therapy and drug resistant Trichomonas vaginalis
1.7 Mechanism of metronidazole resistance in Trichomonas vaginalis
1.8 The proteomics of Trichomonas vaginalis
1.9 Epidemiology of psychiatric disorders
1.10 The association between psychiatric disorders and microbes
1.11 The association between psychiatric disorders and inflammatory diseases
1.12 Motivation
Chapter 2. Materials and Methods
2.1 Data source
2.2 Study design and population
2.3 Covariates
2.4 Incidences of psychiatric disorders
2.5 Trichomonas vaginalis strains and culture conditions
2.6 MTZ resistance assay
2.7 Protein sample preparation and iTRAQ labeling
2.8 LC-MS/MS analysis
2.9 Protein identification
2.10 Proteomic data analysis
2.11 RNA extraction, cDNA synthesis, and quantitative PCR (qPCR)
2.12 ATP synthase inhibition assay
2.13 Statistical analysis
Chapter 3. Results
3.1 Baseline and endpoint demographic characteristics of the selected populations
3.2 Trichomoniasis associates with psychiatric disorders
3.3 Differential risk of psychiatric disorders in subgroups of trichomoniasis patients
3.4 Lower risk of psychiatric disorders for trichomoniasis patients with MTZ treatment
3.5 Higher risk of psychiatric disorders for the subjects with refractory trichomoniasis
3.6 Association of trichomoniasis with other sexually transmitted diseases
3.7 Optimizing MTZ inhibition assay in vitro
3.8 Screening MTZ resistance related proteins by quantitative proteomic analysis and LC-MS/MS
3.9 Select the targets for MTZ resistance by protein-protein interaction network analysis
3.10 Differentially expressed proteins involved in the hydrogenosomal metabolism in the MTZ-R strain
3.11 GSEA revealed altered biological pathways in the MTZ-R proteome after drug treatment
3.12 Several aminotransferases were up-regulated in the MTZ-R strain upon MTZ exposure
3.13 ATP synthase subunit-related proteins were sensitized upon MTZ treatment in the MTZ-S strain
Chapter 4. Discussion
Chapter 5. Conclusion
References
Figure 1. Flowchart of study and control subject’s collection from the Longitudinal Health Insurance Database.
Figure 2. Kaplan-Meier curves for cumulative risk of psychiatric disorders stratified by trichomoniasis with the log-rank test.
Figure 3. A schematic diagram of experimental workflow.
Figure 4. Effects of MTZ on the growth of MTZ-S and MTZ-R T. vaginalis strains.
Figure 5. Functional annotations of the differentially expressed proteins between the MTZ-S and MTZ-R proteomes.
Figure 6. Network and enrichment analysis of the most differentially expressed proteins in the MTZ-R proteome upon MTZ treatment.
Figure 7. Differentially expressed proteins involved in the hydrogenosomal energy metabolism of T. vaginalis in the MTZ-R proteome.
Figure 8. Enrichment analysis of DEP reveals enriched gene sets in the MTZ-R proteome upon MTZ treatment.
Figure 9. ATP synthases subunit proteins are associated with MTZ-resistance.
Table 1. Demographic characteristics of the study and control groups at the baseline.
Table 3. The numbers of psychiatric disorders in the study and control group were shown during the 14 years of follow-up.
Table 4. Risk of psychiatric disorders in the study group
Table 5. Risk of psychiatric disorders in the trichomoniasis subjects
Table 6. Risk of psychiatric disorders subgroup in the trichomoniasis patients treated with MTZ identified by using Cox regression
Table 7. Risk of psychiatric disorders subgroup among study population
Table 8. The most upregulated proteins in the MTZ-R proteome in response to MTZ
Table 9. The most downregulated proteins in the MTZ-R proteome in response to MTZ
Table 10. ATP synthase subunit-related proteins in the oxidative phosphorylation protein set revealed by GSEA
Figure A1. Validation of the proteomic data by qPCR analysis.
Table A1. Abbreviation and ICD-9-CM
Table A2. Demographic characteristics of the study and control populations at the endpoint.
Table A3. Years to the onset of psychiatric disorders
Table A4. Frequency of Trichomoniasis visits
Table A5. Sexually transmitted infections of Trichomoniasis cohort
Table A6. The HIV status of all participants
Table A7. Primers used in this study
Table A8. Differentially expressed proteins in the MTZ-R and MTZ-S proteomes treated with or without MTZ.
Table A9. Differentially expressed proteins involved in the hydrogenosomal energy metabolism in the MTZ-R proteome.
Table A10. Enriched upregulated KEGG pathways in the MTZ-R proteome in response to MTZ treatment
Table A11. Enriched downregulated KEGG pathways in the MTZ-R proteome in response to MTZ treatment
Table A12. Enriched upregulated GO functional annotations in the MTZ-R proteome in response to MTZ treatment
Table A13. Enriched downregulated GO functional annotations in the MTZ-R proteome in response to MTZ treatment
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