Mycobacterium marinum causes a latent infection that can be reactivated by gamma irradiation in adult zebrafish.
Mycobacterium marinum causes a latent infection that can be reactivated by gamma irradiation in adult zebrafish.
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DOI：
10.1371/journal.ppat.1002944
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发表时间：
2012-09
期刊：
影响因子：
6.7
通讯作者：
Rämet M
中科院分区：
文献类型：
--
作者：
Parikka M;Hammarén MM;Harjula SK;Halfpenny NJ;Oksanen KE;Lahtinen MJ;Pajula ET;Iivanainen A;Pesu M;Rämet M
导致人类结核病潜伏和再激活的机制仍然不清楚，主要是由于缺乏标准化的潜伏性分枝杆菌感染的动物模型。在这个纵向研究的进展，分枝杆菌疾病在成年斑马鱼，我们表明，实验性腹腔感染低剂量（1035细菌）的海洋分枝杆菌，结果在发展中的潜伏性疾病，在大多数人。感染的特点是有限的死亡率（25%），稳定的细菌负荷4周后感染和高度组织化的肉芽肿在少数靶器官的恒定数量。大多数细菌在斑马鱼的潜伏性分枝杆菌感染期间处于休眠状态，并且可以通过复苏促进因子离体激活。在5-10%的人类结核病病例中，疾病通常由于免疫抑制而重新激活。在我们的模型中，我们能够证明，通过γ-照射瞬时消耗颗粒/单核细胞和淋巴细胞池，可以有效地诱导感染的斑马鱼的再激活，如通过流式细胞术所确定的。这种免疫抑制导致休眠的分枝杆菌群体的重新激活和细菌的快速生长，导致四周内88%的死亡率。在这项研究中，成年斑马鱼提出了自己作为一个独特的非哺乳动物脊椎动物模型，用于研究潜伏期的发展，分枝杆菌休眠的调节，以及潜伏或亚临床结核病的再激活。筛选影响疾病进展的宿主和病原体因素以及鉴定新的治疗剂和疫苗靶点的可能性使得这种建立的模型特别有吸引力。据估计，世界上有三分之一的人口感染了结核分枝杆菌，在适当的情况下，结核分枝杆菌会导致致命的肺部疾病。根据目前的理解，分枝杆菌可以在宿主中持续存在而不引起症状-这种状态称为潜伏或亚临床感染。然而，如果宿主的免疫系统受到损害，例如由于免疫抑制药物治疗或HIV，疾病可能会重新激活，造成有害后果。导致延迟的机制还没有得到很好的理解。潜伏性结核病对抗生素的反应很差，目前还没有针对潜伏性或再活化结核病的有效疫苗。利用海洋分枝杆菌（Mycobacterium marinum），一种天然的鱼类病原体和M.结核病，我们能够在成年斑马鱼中诱导一种与人类潜伏性疾病非常相似的疾病。我们表明，一个休眠的分枝杆菌种群是存在于动物与潜伏性分枝杆菌疾病。休眠也被认为发生在人类结核病中。此外，我们还提出了一种方法，可以通过实验重新激活潜伏性疾病。尽管人类和鱼类之间存在进化距离，但斑马鱼是研究潜伏期和再激活机制的独特模型。
The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (∼35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5–10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive. One third of the world's population has been estimated to be infected with Mycobacterium tuberculosis, which under the appropriate set of circumstances causes lethal lung disease. According to current understanding, mycobacteria can persist in their host without causing symptoms – a state referred to as latency or subclinical infection. However, if the immune system of the host becomes compromised, for example due to immunosuppressive medical treatments or HIV, the disease can become reactivated with detrimental consequences. The mechanisms leading to latency are not well understood. Latent tuberculosis responds poorly to antibiotics, and there is currently no effective vaccine against latent or reactivated tuberculosis. Using Mycobacterium marinum, a natural fish pathogen and a close relative of M. tuberculosis, we were able to induce a disease in adult zebrafish closely mimicking the human latent disease. We show that a dormant mycobacterial population is present in animals with a latent mycobacterial disease. Dormancy is also thought to occur in human tuberculosis. In addition, we present a method, with which the latent disease can be experimentally reactivated. Despite the evolutionary distance between man and fish, the zebrafish presents itself as a unique model for studying the mechanisms related to latency and reactivation.
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DOI：
10.1084/jem.175.4.1111
发表时间：
1992-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan J;Xing Y;Magliozzo RS;Bloom BR
通讯作者：
Bloom BR
影响因子：
3.1
作者：
Ladel, CH;Blum, C;Kaufmann, SHE
通讯作者：
Kaufmann, SHE
影响因子：
168.9
作者：
Hernández-Pando, R;Jeyanathan, M;Bjune, G
通讯作者：
Bjune, G
影响因子：
--
作者：
Kashino, Suely S.;Ovendale, Pamela;Campos-Neto, Antonio
通讯作者：
Campos-Neto, Antonio
影响因子：
5.8
作者：
Flynn, JoAnne L.
通讯作者：
Flynn, JoAnne L.