Unique model of dormant infection for tuberculosis vaccine development
Unique model of dormant infection for tuberculosis vaccine development
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DOI：
10.1128/cvi.00120-06
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发表时间：
2006-09-01
影响因子：
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通讯作者：
Campos-Neto, Antonio
中科院分区：
文献类型：
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作者：
Kashino, Suely S.;Ovendale, Pamela;Campos-Neto, Antonio
大多数暴露于结核分枝杆菌的个体会被感染，但会阻碍休眠病灶的感染过程，称为潜伏性结核。这种有限的感染通常会刺激强烈的T细胞反应，从而提供对结核病的终身抵抗力。然而，潜伏性结核病仍然知之甚少，特别是因为缺乏可靠的潜伏感染动物模型。在这里，我们表明，接种一个独特的结核分枝杆菌链霉素营养缺陷型突变小鼠重演休眠感染。突变体在链霉素存在下生长不受损害，并且不再生长，但在去除底物后长时间保持活力，从对数生长期转变为潜伏期，如由α-晶状体蛋白的增加的产生所指示的。用突变体激发并接种链霉素约3周的小鼠发生了有限的感染，其特征在于低细菌学负荷和典型肉芽肿的存在。在底物撤出后，感染受到阻碍，但很少有微生物在动物组织中保持存活（休眠）至少6个月。此外，这些动物对M.结核抗原，如早期培养滤液、Ag 85 B和ESAT-6，以及对强毒M.结核因此，小鼠或其他动物（例如，豚鼠）与M.结核菌株18 b构成了一个简单而有吸引力的动物模型，用于在M.结核病易感宿主，这是需要疫苗的人类中普遍存在的一种情况。
Most individuals exposed to Mycobacterium tuberculosis become infected but hinder the infectious process in dormant foci, known as latent tuberculosis. This limited infection usually stimulates strong T-cell responses, which provide lifelong resistance to tuberculosis. However, latent tuberculosis is still poorly understood, particularly because of the lack of a reliable animal model of dormant infection. Here we show that inoculation of mice with a unique streptomycin-auxotrophic mutant of Mycobacterium tuberculosis recapitulates dormant infection. The mutant grows unimpaired in the presence of streptomycin and no longer grows but remains viable for long periods of time after substrate removal, shifting from the log growth phase to the latent stage, as indicated by augmented production of a-crystallin. Mice challenged with the mutant and inoculated with streptomycin for similar to 3 weeks developed a limited infection characterized by a low bacteriological burden and the presence of typical granulomas. After substrate withdrawal, the infection was hindered but few microorganisms remained viable (dormant) in the animals' tissues for at least 6 months. In addition, the animals developed both potent T-cell responses to M. tuberculosis antigens, such as early culture filtrate, Ag85B, and ESAT-6, and resistance to reinfection with virulent M. tuberculosis. Therefore, infection of mice or other animals (e.g., guinea pigs) with M. tuberculosis strain 18b constitutes a simple and attractive animal model for evaluation of antituberculosis vaccines in the context of an M. tuberculosis-presensitized host, a prevailing condition among humans in need of a vaccine.