Antisense Mutants of M. Tuberculosis

描述(由申请人提供) 分枝杆菌遗传学的进展使改变致病的M。 结核菌株创造新的候选疫苗。我们已经建造了 结核分枝杆菌强毒株H37Rv突变体的缺失 生产铁-锰超氧化物歧化酶(SOD)。这些菌株是 小鼠对卡介苗的耐受性比卡介苗好，当作为疫苗注射时， 与卡介苗相比，对后续感染强毒M。 结核病，几乎消除了对肺的破坏 以肺结核为特征。此应用程序的重点是 阐明我们的超氧化物歧化酶降低疫苗效果的机制 H37Rv株与卡介苗的比较。我们假设有两个主要因素 牵涉其中。首先是卡介苗缺乏的H37Rv产生关键抗原。 第二个是抗原提呈机制的不同，大多数 可能与凋亡相关的MHC I类抗原处理，从而增强 超氧化物歧化酶基因敲除H37Rv株激发更强免疫的效果 对卡介苗和H37Rv共同抗原的反应。这项工作的重点是 涉及到阐明这些因素的相对重要性，以及具体的 目标包括：(1)确定减少的直接影响 SOD产生对疫苗效力和免疫保护相关因素的影响；(2) 评估品种和菌株差异对疫苗的重要性 抑制超氧化物歧化酶的结核分枝杆菌复合菌株的疗效 针对其他结核分枝杆菌复合体产生的交叉保护量 菌株；以及(3)确定修饰超氧化物歧化酶是否减少卡介苗和超氧化物歧化酶 牛分枝杆菌通过添加牛分枝杆菌所特有的特定抗原。 结核病提高了对致病性结核分枝杆菌的疫苗效力。这个 这项工作的发现将有助于优化疫苗效果，还可能 扩展我们的诊断能力，以区分以前接种过的疫苗和 肺结核感染。

DESCRIPTION (provided by applicant) Advances in mycobacterial genetics have made it feasible to alter virulent M. tuberculosis strains to create novel vaccine candidates. We have constructed mutants of the virulent M. tuberculosis strain H37Rv exhibiting diminished production of iron-manganese superoxide dismutase (SOD). These strains are tolerated better than BCG by mice and when administered as a vaccine, confer greater protection than BCG against subsequent infection with virulent M. tuberculosis, virtually eliminating the lung destruction that is characteristic of pulmonary tuberculosis. The focus of this application is to elucidate the mechanism of superior vaccine efficacy of our SOD-diminished H37Rv strains compared to BCG. We hypothesize that two major factors are involved. The first is the production of key antigens by H37Rv that BCG lacks. The second is a difference in the mechanism of antigen presentation, most likely apoptosis-associated MHC Class I antigen processing, that enhances the efficacy of the SOD-diminished H37Rv strain by stimulating a stronger immune response to antigens common to both BCG and H37Rv. The focus of this work involves elucidating the relative importance of these factors, with specific objectives that include: (1) To determine the direct effect of diminishing SOD production upon vaccine efficacy and immune correlates of protection; (2) To assess the importance of species and strain differences upon the vaccine efficacy of SOD-diminished M. tuberculosis complex strains including the amount of cross-protection generated against other M. tuberculosis complex strains; and (3) To determine whether modifying SOD-diminished BCG and SODdiminished M. bovis by adding specific antigens that are unique to M. tuberculosis improves vaccine efficacy against virulent M. tuberculosis. The findings from this work will help to optimize vaccine efficacy and may also expand our diagnostic capacity to distinguish prior vaccination from tuberculosis infection.