The Study of Host-Related Factors in Infection of Mycobacterium tuberculosis

• Main Authors: Hsu, Ai-Hsi, 胥愛璽
• Other Authors: Chen, Li-Kuang
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/76522430679624501243

博士 === 慈濟大學 === 醫學科學研究所 === 101 === 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.