Mycobacteria exploit host hyaluronan for efficient extracellular replication.
Mycobacteria exploit host hyaluronan for efficient extracellular replication.
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DOI：
10.1371/journal.ppat.1000643
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发表时间：
2009-10
期刊：
影响因子：
6.7
通讯作者：
Matsumoto S
中科院分区：
文献类型：
--
作者：
Hirayama Y;Yoshimura M;Ozeki Y;Sugawara I;Udagawa T;Mizuno S;Itano N;Kimata K;Tamaru A;Ogura H;Kobayashi K;Matsumoto S
尽管透明质酸在保护宿主免受肺泡腔中的感染性生物体的重要性，但其在分枝杆菌感染中的作用尚不清楚。在以前的研究中，我们发现分枝杆菌与肺上皮细胞上的透明质酸相互作用。在这里，我们分析了透明质酸在分枝杆菌感染后的作用，发现致病分枝杆菌可以利用透明质酸作为碳源生长。小鼠和人类都具有3种透明质酸酶（HAS），命名为HAS 1、HAS 2和HAS 3。利用单个的HAS转染细胞，我们发现HAS 1和HAS 3而不是HAS 2支持分枝杆菌的生长。我们发现肺中表达的主要透明质酸合酶是HAS 1，并且在结核分枝杆菌感染后其表达增加。组织化学分析显示透明质酸在M.感染结核病的小鼠和死于结核病的恒河猴。我们检测了分枝杆菌裂解液中透明质酸酶的活性，并表明它对透明质酸依赖性细胞外生长至关重要。最后，我们发现L-抗坏血酸6-十六烷酸酯，透明质酸酶抑制剂，抑制体内分枝杆菌的生长。总之，我们的数据表明，致病性分枝杆菌利用内在的宿主保护分子，透明质酸，在呼吸道中生长，并证明透明质酸酶抑制剂对分枝杆菌疾病的潜在有用性。 结核分枝杆菌（Mycobacterium tuberculosis）和牛分枝杆菌（Mycobacterium bovis）是主要的细菌病原体，每年通过引起结核而杀死大约200万人。分枝结核复合体有几种寄生宿主的策略。在感染建立后，这些病原体很少从宿主中消除，如今世界上大约三分之一的人口感染了结核分枝杆菌复合体。阐明了该虫的寄生机理。结核病综合征的研究对于开发对抗该疾病的新策略非常重要。M.肺结核是通过呼吸道传播的。在气道表面，透明质酸保留了杀菌酶，使它们“随时可用”，保护组织免受入侵的病原体。此外，由于感染而产生的片段化透明质酸被免疫系统用作感染的传感器。因此，透明质酸在呼吸道中的宿主防御中起关键作用。然而，在这项研究中，我们观察到，M。结核复合体利用透明质酸作为增殖的碳源。我们还发现M.结核杆菌复合物具有透明质酸酶活性，并表明它对透明质酸依赖性生长的M.肺结核综合征这项研究表明了一种新的寄生机制的M。结核复合体，并建议分枝杆菌透明质酸酶是一个潜在的药物靶标。
In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases. Mycobacterium tuberculosis and Mycobacterium bovis are major bacterial pathogens that kill approximately 2 million people annually by causing tuberculosis. The M. tuberculosis complex has several strategies to parasitize the host. After infection is established, these pathogens are rarely eliminated from the host, and nowadays approximately a third of the world's human population is infected with the Mycobacterium tuberculosis complex. The elucidation of the parasitic mechanisms of the M. tuberculosis complex is important for the development of novel strategies against the disease. The major portal entry of M. tuberculosis complex is through the respiratory tract. On the surface of the airway, hyaluronan retains bactericidal enzymes so that they are “ready-to-use”, protecting tissues from invading pathogens. Furthermore, fragmented hyaluronan produced as a result of infection is used by the immune system as a sensor of infection. Thus, hyaluronan plays a pivotal role in host defenses in the respiratory tract. However, in this study, we observed that the M. tuberculosis complex utilizes hyaluronan as a carbon source for multiplication. We also found that the M. tuberculosis complex has hyaluronidase activity and showed that it is critical for hyaluronan-dependent growth of the M. tuberculosis complex. This study demonstrates a novel parasitic mechanism of the M. tuberculosis complex and suggests that mycobacterial hyaluronidase is a potential drug target.
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DOI：
10.1084/jem.180.1.53
发表时间：
1994-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bartolazzi A;Peach R;Aruffo A;Stamenkovic I
通讯作者：
Stamenkovic I
结核分枝杆菌的外塞蛋白从人体结合蛋白中去除铁，并将铁捐赠给结核分枝杆菌细胞壁中的霉菌素。
影响因子：
15.3
作者：
Gobin, J;Horwitz, MA
通讯作者：
Horwitz, MA
影响因子：
56.9
作者：
JACOBS, WR;BARLETTA, RG;BLOOM, BR
通讯作者：
BLOOM, BR
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：
3.2
作者：
Katsube, Tomoya;Matsumoto, Sohkichi;Kobayashi, Kazuo
通讯作者：
Kobayashi, Kazuo