Mycothiol Associated Genes in ROI and RNI Stress Response

结核病(TB)是世界上导致200万人死亡的微生物病原体的主要死因。 每年都有人。世界上三分之一的人口感染结核分枝杆菌， 结核病(TB)的病原体。免疫功能受损的人，如那些被诊断为 感染艾滋病毒和无家可归的人得不到医疗护理的风险更大 发展成结核病。此外，尽管可以进行结核病的药物治疗，但依从率很低，而且 导致多重耐药菌株的出现。出于这些原因，结核病再次成为一种公共卫生 威胁和新的科学兴趣重新出现在识别毒力因素，帮助 病原学这种有机体的致病机理 结核分枝杆菌是一种兼性胞内有机体，在 宿主免疫系统的巨噬细胞。巨噬细胞杀死微生物的方式之一是通过 释放对微生物有害的活性氧和氮物种。在这项研究中 建议，编码过氧化还蛋白、谷氧还蛋白等酶的基因，以及 亚硝硫醇还原酶，保护免受氧化和亚硝化应激，从而帮助 巨噬细胞中的分枝杆菌将被研究。特别是，需要麦硫醇的酶，一种独特的硫醇 它只存在于放线菌中，是分枝杆菌细胞所必需的，将被研究。M 将在编码这些霉菌硫醇依赖基因的基因中创建针对牛卡介苗的突变体 验证基因功能并确定这些基因在发病机制中的作用。转座子突变体文库 还将创建和筛选对二硫化物胁迫敏感的突变株，这将 导致细胞中硫醇的耗尽。牛分枝杆菌卡介苗，结核分枝杆菌疫苗株， 是研究生物安全二级控制中结核分枝杆菌毒力因子的模式生物。

Tuberculosis (TB) is the leading cause of death among microbial agents in the world killing two million people annually. One-third of the world population is infected with Mycobacterium tuberculosis, the causative agent of the disease tuberculosis (TB). Immunocompromised individuals such as those diagnosed with HIV infections and the homeless who do not have access to medical care are at a greater risk for developing TB. In addiiton, although drug therapy for TB is available, compliance rates are low and have resulted in the emergence of multi-drug resistant strains. For these reasons, TB is again a public health threat and there is a renewal of scientific interest in the identification of virulence factors that aid in the pathogenesis of this organism. Mycobacterium tuberculosis is a facultative intracellular organism that resides and replicates within the macrophages of the host immune system. One of the ways the macrophage kills microorganisms is by releasing reactive oxygen and nitrogen species that are harmful to the microorganism. In this research proposal, genes coding for such enzymes as peroxiredoxins, glutaredoxin like "mycoredoxins", and nitrosothiol reductase that protect against oxidative and nitrosative stress and therefore aid in the survival of mycobacteria in macrophages will be investigated. In particular, enzymes requiring mycothiol, a unique thiol that is present exclusively in Actinomycetes and is essential to the mycobacterial cell, will be studied. M bovis BCG targeted mutants will be created in genes that encode these mycothiol dependent genes to validate gene function and to determine the role of these genes in pathogenesis. A transposon mutant library of M. bovis BCG will also be created and screened for mutants sensitive to disulfide stress which would result in the depletion of thiols in the cell. Mycobacterium bovis BCG, the vaccine strain for M. tuberculosis, is a model organism for studying M. tuberculosis virulence factors in Biosafety Level 2 containment.