Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells.
Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells.
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DOI：
10.1371/journal.ppat.0030110
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发表时间：
2007-07
期刊：
影响因子：
6.7
通讯作者：
Briken V
中科院分区：
文献类型：
--
作者：
Velmurugan K;Chen B;Miller JL;Azogue S;Gurses S;Hsu T;Glickman M;Jacobs WR Jr;Porcelli SA;Briken V
结核分枝杆菌的存活和持久性取决于其操纵多种宿主防御途径的能力，包括主动抑制受感染宿主细胞凋亡导致的死亡的能力。这种抗凋亡活性的遗传基础及其对分枝杆菌毒力的影响尚未得到证实或阐明。利用一种新的功能获得性基因筛选，我们证明了感染诱导的巨噬细胞凋亡的抑制是由M.结核对其中一个位点的详细表征表明，抗凋亡活性可归因于M.结核病，并主要是由于这种多组分复合物的亚单位编码的nuoG基因。表达M.非致病性分枝杆菌中的结核nuoG赋予它们抑制感染的人或小鼠巨噬细胞凋亡的能力，并增加它们在SCID小鼠模型中的毒力。相反，在M.结核病消除了其抑制巨噬细胞凋亡的能力，并显著降低了其在小鼠中的毒力。这些结果确定了一个关键组成部分的遗传基础的一个重要的毒力性状的M。结核病和支持致病性分枝杆菌的毒力和它们抑制巨噬细胞凋亡的能力之间的直接因果关系。在细胞内病原体入侵后，感染诱导的宿主细胞自杀是在动物和植物界的多细胞生物中观察到的古老防御机制。因此，病毒、细菌和原生动物来源的持久性病原体进化为抑制宿主细胞死亡的诱导并不奇怪。M.结核病是结核病的病原体，它潜伏地感染了世界上大约三分之一的人口，并且可以在受感染的无症状个体的肺中持续数十年。在本研究中，我们已经确定了nuoG的M。结核病，其编码I型NADH脱氢酶复合物的亚基，作为抑制宿主细胞死亡的关键细菌基因。M. nuoG被删除的结核病引发了感染的巨噬细胞凋亡的显着增加，随后在小鼠结核病模型中对该突变体的分析为抑制凋亡的能力和细菌毒力之间的因果关系提供了直接证据。M.结核病可以提供一种强有力的方法来产生更好的减毒疫苗株，也可以确定一组新的药物靶点，以改善化疗。
The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis. The infection-induced suicide of host cells following invasion by intracellular pathogens is an ancient defense mechanism observed in multicellular organisms of both the animal and plant kingdoms. It is therefore not surprising that persistent pathogens of viral, bacterial, and protozoal origin have evolved to inhibit the induction of host cell death. M. tuberculosis, the etiological agent of tuberculosis, has latently infected about one third of the world's population and can persist for decades in the lungs of infected, asymptomatic individuals. In the present study we have identified nuoG of M. tuberculosis, which encodes a subunit of the type I NADH dehydrogenase complex, as a critical bacterial gene for inhibition of host cell death. A mutant of M. tuberculosis in which nuoG was deleted triggered a marked increase in apoptosis by infected macrophages, and subsequent analysis of this mutant in the mouse tuberculosis model provided direct evidence for a causal link between the capacity to inhibit apoptosis and bacterial virulence. The discovery of anti-apoptosis genes in M. tuberculosis could provide a powerful approach to the generation of better attenuated vaccine strains, and may also identify a new group of drug targets for improved chemotherapy.
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影响因子：
3.4
作者：
Derrick, Steven C.;Morris, Sheldon L.
通讯作者：
Morris, Sheldon L.
影响因子：
2.8
作者：
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DOI：
10.1164/ajrccm.164.12.2106093
发表时间：
2001-12-15
影响因子：
24.7
作者：
Edwards, KM;Cynamon, MH;Kernodle, DS
通讯作者：
Kernodle, DS
影响因子：
4.4
作者：
Kausalya, S;Somogyi, R;Prystowsky, MB
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