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性分枝杆菌成为可能。 结核菌株，以创造新的候选疫苗。我们已经构建 突变体的毒性M.结核菌株H37 Rv表现出减少的 生产铁锰超氧化物歧化酶（SOD）。这些菌株 小鼠耐受性优于BCG，当作为疫苗施用时， 比BCG更好地防止随后感染强毒M。 肺结核，几乎消除了肺破坏， 以肺结核为特征。此应用程序的重点是 阐明了我们的SOD减少的上级疫苗效力的机制 H37 Rv菌株与BCG相比。我们假设两个主要因素是 涉案第一个是H37 Rv产生BCG缺乏的关键抗原。 第二个是抗原呈递机制的差异，大多数 可能与乳腺癌相关的MHC I类抗原加工， SOD减少的H37 Rv菌株通过刺激更强的免疫应答的功效 对BCG和H37 Rv共同抗原的反应。这项工作的重点 包括阐明这些因素的相对重要性， 目标包括：（1）确定减少的直接影响 SOD的产生对疫苗效力和保护的免疫相关性的影响;（2） 评估种属和毒株差异对疫苗的重要性 SOD减少M.的功效结核复合菌株，包括 对其他M产生的交叉保护量。结核复合物 （3）确定修饰SOD是否减少BCG和SOD是否减少 M.牛支原体的特异性抗原。 结核病提高了疫苗对强毒M.结核的 这项工作的发现将有助于优化疫苗的功效， 扩大我们的诊断能力，以区分先前的疫苗接种， 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.