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PLoS Pathog:结核病中导致严重肺损伤的宿主基因

  1. 宿主基因
  2. 结核病中
  3. 肺损伤

来源:生物谷 2014-07-11 13:46

全球三分之一人口感染了一种细菌病原体--结核分枝杆菌,导致结核病(TB)。发表于PLOS Pathogens杂志上的一则研究文章现在确定:在结核病中,加剧严重肺损伤的宿主因素。为了了解积极结核病的根本机制,巴西圣保罗大

2014年7月5日讯 /生物谷BIOON/--全球三分之一人口感染了一种细菌病原体--结核分枝杆菌,其导致结核病(TB)。发表于PLOS Pathogens杂志上的一则研究文章现在确定:在结核病中,加剧严重肺损伤的宿主因素。

为了了解积极结核病的根本机制,巴西圣保罗大学Elena Lasunskaia和同事研究了模拟结核病的有严重肺部症状的小鼠模型。像人类患者,感染了两种不同的高毒性分枝杆菌菌株的小鼠,肺发生坏死性病变,死细胞破开并释放其内容物。坏死碎片包含促进宿主大量免疫细胞涌入的分子,由此产生局部炎症造成进一步损害肺组织。

坏死碎屑的内容物之一是能量存储分子ATP,当在细胞外发现时,通过结合P2X7受体(P2X7R)以刺激免疫细胞。研究人员分析在严重形式结核病中这种分子途径作用是否与肺坏死相关。他们研究缺乏P2X7R小鼠,结果发现这些老鼠能存活。

更详细的分析表明,P2X7R在结核病发展中起到双重作用。首先,它似乎通过杀死被感染的免疫细胞,促进释放那些在此过程中幸存下来的分枝杆菌的内容物,以促进高毒性分枝杆菌的传播。其次,P2X7R也似乎通过促进广泛的组织破坏,导致肺部炎症和损伤。

没有P2X7R的小鼠感染高毒性分枝杆菌后会有更好的结果。当研究人员用具有较少攻击性的结核病菌株感染小鼠,他们发现P2X7R实际上有助于控制这种感染。在这种情况下,P2X7R-介导的免疫细胞刺激并没有导致细胞死亡以及释放能独立生存的分枝杆菌,所以实际上是遏制感染,而不是将其传播。

P2X7R对肺部感染高毒性和不太积极分枝杆菌菌株有相反的效果,P2X7R等位基因丧失功能(即P2X7R基因变体缺陷)是在人类中常见的,它们与肺结核风险较高相关。根据他们的结果,研究人员认为,这种变异可能会增加轻度肺结核的风险,但降低严重结核病的风险。

他们还指出,他们的研究提供一种观点,抑制P2X7R药物可用来改善积极形式结核病的结果。(生物谷Bioon.com)

Pulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosis

Amaral EP, Ribeiro SCM, Lanes VR, Almeida FM, de Andrade MRM, et al.

The purinergic P2X7 receptor (P2X7R) is a sensor of extracellular ATP, a damage-associated molecule that is released from necrotic cells and that induces pro-inflammatory cytokine production and cell death. To investigate whether the innate immune response to damage signals could contribute to the development of pulmonary necrotic lesions in severe forms of tuberculosis, disease progression was examined in C57BL/6 and P2X7R-/- mice that were intratracheally infected with highly virulent mycobacterial strains (Mycobacterium tuberculosis strain 1471 of the Beijing genotype family and Mycobacterium bovis strain MP287/03). The low-dose infection of C57BL/6 mice with bacteria of these strains caused the rapid development of extensive granulomatous pneumonia with necrotic areas, intense bacillus dissemination and anticipated animal death. In contrast, in P2X7R-/- mice, the lung pathology presented with moderate infiltrates of mononuclear leukocytes without visible signs of necrosis; the disease attenuation was accompanied by a delay in mortality. In vitro, the hypervirulent mycobacteria grew rapidly inside macrophages and induced death by a P2X7R-dependent mechanism that facilitated the release of bacilli. Furthermore, these bacteria were resistant to the protective mechanisms elicited in macrophages following extracellular ATP stimulation. Based on this study, we propose that the rapid intracellular growth of hypervirulent mycobacteria results in massive macrophage damage. The ATP released by damaged cells engages P2X7R and accelerates the necrotic death of infected macrophages and the release of bacilli. This vicious cycle exacerbates pneumonia and lung necrosis by promoting widespread cell destruction and bacillus dissemination. These findings suggest the use of drugs that have been designed to inhibit the P2X7R as a new therapeutic approach to treat the aggressive forms of tuberculosis.

 

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