臺灣博碩士論文加值系統

結核病新個案在東台灣(花東)年發生率明顯高於台灣的平均發生率，因此研究的主題於第一章先探討結核菌於宿主間的群聚感染。利用分子流病的方式，結合spoligotying及Mycobacterial interspersed repetitive unit- variable tandem-repeat (MIRU-VNTR)兩種 polymerase chain reaction 為基礎的技術，鑑定結核菌的基因型來探討多重抗藥肺結核(MDRTB)於東台灣的流病傳播狀況。結果顯示於東台灣就MDRTB的傳染有61.6%的群聚感染現象。MDRTB可能有能力於宿主間產生群體間的傳染。

延續結核菌感染與宿主間相關因素的子題，於第二章探討糖尿病病患(個體免疫) 感染結核菌之相關主題探討。糖尿病病人免疫不佳所以容易再度治療，比較新感染個案，糖尿病與isoniazid抗藥菌株之相關於結核再治(retreat)個案較多見(odd ratio:6.76)。但於此回溯性研究或因樣本數不足，並未能顯示MDRTB於新發生或再度發生肺結核之群體，與糖尿病的明顯相關性。

第三章中，我們以動物模式於分子分析層面來探討宿主対結核的防禦機轉。
吲哚胺2,3雙加氧酶1（Indoleamine 2,3-dioxygenase; IDO3-dioxygenase; IDO1）是色胺酸代謝路徑的速率決定酵素，並可以扮演免疫負向調控因子，通過誘發增殖免疫調節T 細胞 (regulatory T cells)，進而調節免疫反應。IDO 1通過與調節性T細胞(regulatory T cells) 直接接觸並相互作用，對調控CD4 T細胞譜系分化與專一性 Foxp3的發展，是至關重要的。色氨酸代謝物能參與Th1和Th17細胞的發展分化。IDO1基因如何影響免疫調控於肺結核感染的疾病模式，以及其機制，於目前的文獻中，較少被探討。在本論文的實驗模式下，於實驗證明，於IDO1基因敲除小鼠與其對應的C57BL/6之對照組，當予以不同劑量之結核菌感染時，可能導致包括死亡率及其他表現型之差異。IDO1基因敲除小鼠，雖然其於結核桿菌感染狀況下，其色氨酸酶降解之功能可通過其他途徑，於結核感染後期恢復，但是，IDO1的免疫調節能力卻不能被取代。經口鼻路徑，吸入含1600CFU結核桿菌氣霧，IDO1基因敲除小鼠對照其對應的C57BL/6之小鼠，其早期的死亡率較高，但於IDO1基因敲除小鼠機體器官並未表現明顯較高的結核桿菌菌落形成單位(CFU/ml)。於IDO1基因敲除小鼠，較多的嗜中性白血球細胞持續湧入肺部，吾等假設這至少與肺部較多Th17和IL-17a 所導致的化學驅化性相關。於1600CFU高劑量結核桿菌感染下，嗜中性白血球細胞持續湧入IDO1基因敲除小鼠肺部，。目前有相關研究顯示嗜中性白血球細胞可於特定情況下分泌IL-10，而造成免疫抑制。本實驗並探索IDO2對於結核菌感染的相關反應。

The annual incidence of new pulmonary tuberculosis cases in Eastern Taiwan was significantly higher than average incidence across Taiwan. In the first chapter, the theme of the research is to explore Mycobacterium tuberculosis (Mtb) outbreaks amongst hosts. Take advantage of the molecular tools combined spoligotying and mycobacterial interspersed repetitive unit-variable tandem-repeat (MIRU-VNTR), two PCR-based techniques, we may identify Mtb genotype and explore the multi drug-resistant tuberculosis (MDRTB) transmission in Eastern Taiwan. The results showed a 61.6% cluster ratio between MDRTB infected subjects in Eastern Taiwan, especially amongst indigenous groups. MDR strains might cause widespread transmission contrasted with the previous view that MDR-TB was less infectious.

In chapter 2, we intend to investigate if diabetes mellitus (DM) is correlated with the infection of drug-resistant tuberculosis strains. Also, we stratified the subjects according to their tuberculosis treatment history. The host immunity of diabetic patients may be poor compare to those without diabetes; more diabetic subjects are supposed to be re-treated for tuberculosis infection. Irrespective of new or previously treated status, DM was found to be significantly associated with isoniazid-related resistant strains of tuberculosis both in new and re-treated subjects, which showed an adjusted odd ratio: 6.76 compared to those without DM. In this retrospective investigation, we did not find the significant association between DM and MDRTB, which may be attributed to the limited sample size.

In chapter 3, we animal model was utilized to investigate defense mechanism of host against tuberculosis infection via a molecular perspective. Indoleamine 2,3-dioxygenase 1 (IDO1) is as a rate limiting enzyme in tryptophan metabolism and could exert a tolerogenic function in regulating the immune system. So far, no evidence proved that IDO1 can exert a killing effect against M. tuberculosis in vivo despite the fact that IDO1 own antimicrobial property against some pathogenic microbes. In this thesis, relevant experiments were conducted majorly upon its immuno-regulatroy effect in the mice model. IDO1 interacts with regulatory T cell by a direct contact fashion and is crucial in specifying to the development of a Foxp3 positive regulatory lineage during the CD4+ T cell lineage differentiation; in addition, tryptophan metabolites were reportedly to participate in the development of Th1 and Th17 cell differentiation. The mechanisms how IDO1 gene regulate the immune homeostasis in tuberculosis infection were less documented. In our preliminary data, tuberculosis infection might lead to distinct difference in mortality between IDO1 knockout mice and their counterparts with C57BL/6 background. Thus far we have shown that enzymatic degradation of tryptophan might be restored by alternative pathways in later stage of Mtb infection in IDO1-/- mice. However, its immune modulating ability may not be replaced and contributed to the distinct mortality phenotypes. Moreover, different doses of Mtb antigens exposure might act significantly in host’s immune homeostasis, which has shown in our study to influence the mortality between IDO1-/- and WT mice. In 1600CFU Mtb CFU infection via aerosol route, there was an earlier mortality in IDO1 -/- mice; a persistent higher proportion of neutrophil influx into the lungs, which was assumed at least to be link with Th17 lineage specification and IL-17a chemo-attraction. Also, the mortality was suspected to be partially associated with the IL-10 production of neutrophils. In this study, we also investigated the IDO2 response to Mtb infection.

中文摘要_____________________________________________________________________________ 7
English Abstract_______________________________________________________________________ 9
Chpater 1 Molecular Epidemiology of Multidrug-Resistant Mycobacterium tuberculosis in Eastern Taiwan
1. General Introduction _______________________________________________________________ 11
2. Materials and Methods________________________________________________________________ 12
2.1 Study setting _____________________________________________________________________ 12
2.2 Patient characteristic ______________________________________________________________ 12
2.3 Bacterial isolates and DNA extraction ________________________________________________ 12
2.4 Spoligotyping _____________________________________________________________________ 13
2.5 MIRU-VNTR genotyping ___________________________________________________________ 13
2.6 Drug susceptibility testing ___________________________________________________________ 14
2.7 Definition of MDR-TB transmission ___________________________________________________ 14
2.8 Statistical analysis and clustering assignment ___________________________________________ 15
3. Results _________________________________________________________________________ 15
4. Discussion ________________________________________________________________________ 17
5. Conclusion ___________________________________________________________________________ 19

Chapter II Diabetes is associated with Drug Resistant Tuberculosis in Eastern Taiwan
1. General Introduction ________________________________________________________________ 20
2. Materials and Methods ________________________________________________________________ 20
2.1. Study setting _______________________________________________________________________ 20
2.2. Respiratory specimen processing drug susceptibility testing _______________________________ 20
2.3. Statistical analysis. __________________________________________________________________ 21
3. Results _________________________________________________________________________ 21
4. Discussion _________________________________________________________________________ 22
5. Conclusion _________________________________________________________________________ 23

Chapter III Indoleamine 2,3-dioxygenase 1 (IDO1) knockout does not change the ability of the host to kill M.tuberculosis but lead to excessive inflammation causes the death of C57 mice
1. General Introduction ____________________________________________________________________ 24
1.1. Background of Indoleamine 2,3-dioxygenase ____________________________________________ 24
1.2. Antimicrobial property of Indoleamine 2,3-dioxygenase ___________________________________ 24
1.3. Immunoregulatory property of Indoleamine 2,3-dioxygenase _______________________________ 25
1.4. Immuno-phenotypes at IDO1 gene knockout mice with M. tuberculosis infection_______________ 26
1.5. IDO1 and IDO2 response to tuberculosis infection ________________________________________ 27
2. Materials and Methods _________________________________________________________________ 28
2.1. Animal infections __________________________________________________________________ 29
2.2. Cell isolation and flow-cytometry analysis _______________________________________________ 29
2.3. Histology and immunohistochemistry of IDO2 _________________________________________ 29
2.4. Real-time PCR for mRNA expression __________________________________________________ 29
2.5. High performance liquid chromatography _____________________________________________ 30
2.6. Statistical analysis ___________________________________________________________________ 32
3. Results________________________________________________________________________________ 32
3.1. The mortality curves and organ Mtb CFU with 100 CFU Mtb infection
at IDO1 -/- and WT/B6 mice __________________________________________________________ 32
3.2. The total cell , CD4 positive T cells and Treg cell numbers at the lung
and MLN with 100 CFU Mtb infection __________________________________________________ 32
3.3. IL-17a secretary cell population at the lungs with 100 CFU Mtb infection _____________________ 34
3.4. The mice mortality and organ Mtb CFU with 1000CFU Mtb infection _______________________ 34
3.5. The cell numbers of the lung and MLN with 1000CFU Mtb infection __________________________ 34
3.6. The CD4+lymphocytes, Treg percentages and numbers at the lung
and MLN with 1000 CFU Mtb infection ___________________________________________________ 34
3.7. With 1000 CFU Mtb infection, IL-17a cells profiles including Th17 and γδT cells ________________ 34
3.8. The mice mortality and organ Mtb CFU with Mtb 1600CFU infection._________________________ 34
3.9. Total cell number in lung and MLN of mice with 1600 CFU Mtb infection ____________________ 35
3.10. CD4, CD8, Treg, γδT cell percentage and numbers at the lung and MLN
with 1600 CFU Mtb infection ________________________________________________________ 35
3.11. IL-17a positive cells profiles at the lung with 1600 CFU Mtb infection ______________________ 35
3.12. The neutrophil at the lungs and MLN with 100, 1000 and 1600CFU Mtb Infection ___________ 36
3.13. Cytokines mRNA relative expression at the lung with 100, 1000 and 1600 CFU Mtb infection __ 36
3.14. IDO expression in mice with 100 CFU Mtb infection ____________________________________ 36
3.15. IDO gene expression in mice with 100, 1000, and 1600 CFU Mtb infection___________________ 37
3.16. Serum kynurenine and tryptophan ration by HPLC to scrutinize the IDO enzymatic function _ 37
3.17. The impact of IDO inhibitors amonsgt 100 CFU Mtb infected mice ________________________ 38
4. Discussion _____________________________________________________________________________ 39
5. Conclusion_______________________________________________________________________________ 43
6. Reference________________________________________________________________________________ 44
7. Figures and Tables _______________________________________________________________________ 54

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