Neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with burkholderia species.
Neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with burkholderia species.
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DOI：
10.1371/journal.ppat.1004327
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发表时间：
2014-08
期刊：
影响因子：
6.7
通讯作者：
Re F
中科院分区：
文献类型：
--
作者：
Sahoo M;Del Barrio L;Miller MA;Re F
两种不同的防御策略可以保护宿主免受感染：抗性是破坏感染因子的能力，耐受性是通过最小化感染对宿主健康的负面影响而不直接影响病原体负担来抵御感染的能力。类鼻疽伯克霍尔德菌是一种革兰氏阴性细菌，感染巨噬细胞并引起类鼻疽病。我们最近的研究表明，炎性小体引发的细胞凋亡和IL-18对于B的耐药性同样重要。假鼻疽，而IL-1β是有害的。在这里，我们表明IL-1β在B感染过程中的有害作用。伪鼻疽（与B密切相关。Thailandensis）是由于嗜中性粒细胞过度募集到肺和随之而来的组织损伤。尽管C57 BL/6 J和弹性蛋白酶缺陷小鼠之间器官中的细菌负荷和炎症程度相当，但缺乏潜在破坏性酶中性粒细胞弹性蛋白酶的小鼠比野生型C57 BL/6 J小鼠对感染的敏感性更低。相反，与对照组相比，弹性蛋白酶缺陷小鼠的肺组织损伤和血管渗漏显著减少。缓激肽水平在C57 BL/6高于弹性蛋白酶缺陷小鼠;缓激肽拮抗剂的管理保护小鼠免受感染，这表明缓激肽介导的血管通透性增加是弹性蛋白酶降低宿主对类鼻疽的耐受性的机制之一。总的来说，这些结果表明，中性粒细胞弹性蛋白酶的缺乏通过最小化宿主组织损伤来增加宿主对感染的耐受性，而不是抗性。两种不同的防御策略可以保护宿主免受感染：抗性是破坏感染因子的能力，耐受性是通过最小化感染对宿主健康的负面影响而不直接影响病原体负担来抵御感染的能力。类鼻疽伯克霍尔德菌是类鼻疽病的病原体，是一种革兰氏阴性细胞内细菌，被归类为潜在的生物恐怖主义制剂。使用小鼠模型，我们以前证明，在B。在类鼻疽感染中，IL-1β的产生是有害的，因为它将过量的中性粒细胞募集到感染部位。在目前的工作中，我们集中在中性粒细胞在感染B的有害作用。类鼻疽和B.泰国茶在这里，我们证明了中性粒细胞过度募集到感染部位会导致组织损伤，因为蛋白酶弹性蛋白酶的释放。与野生型C57 BL/6 J相比，缺乏中性粒细胞弹性蛋白酶的小鼠即使在其器官中携带等量的细菌也能提高存活率。因此，嗜中性粒细胞弹性蛋白酶是一种宿主防御机制，可引起组织损伤并降低宿主对感染的耐受性。
Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and causes melioidosis. We have recently shown that inflammasome-triggered pyroptosis and IL-18 are equally important for resistance to B. pseudomallei, whereas IL-1β is deleterious. Here we show that the detrimental role of IL-1β during infection with B. pseudomallei (and closely related B. thailandensis) is due to excessive recruitment of neutrophils to the lung and consequent tissue damage. Mice deficient in the potentially damaging enzyme neutrophil elastase were less susceptible than the wild type C57BL/6J mice to infection, although the bacterial burdens in organs and the extent of inflammation were comparable between C57BL/6J and elastase-deficient mice. In contrast, lung tissue damage and vascular leakage were drastically reduced in elastase-deficient mice compared to controls. Bradykinin levels were higher in C57BL/6 than in elastase-deficient mice; administration of a bradykinin antagonist protected mice from infection, suggesting that increased vascular permeability mediated by bradykinin is one of the mechanisms through which elastase decreases host tolerance to melioidosis. Collectively, these results demonstrate that absence of neutrophil elastase increases host tolerance, rather than resistance, to infection by minimizing host tissue damage. Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei, the causative agent of melioidosis, is a Gram-negative intracellular bacteria that is categorized as a potential bioterrorism agent. Using murine models, we previously demonstrated that during B. pseudomallei infection, production of IL-1β is deleterious as it recruited excessive neutrophils to the site of infection. In the present work, we focused on the detrimental role of neutrophils during infection with B. pseudomallei and B. thailandensis. Here, we demonstrate that the excessive recruitment of neutrophils to the site of infection causes tissue damage because of release of the protease elastase. Mice lacking neutrophil elastase have increased survival even though they carry an equal amount of bacteria in their organs as compared to the wild-type C57BL/6J. Thus, neutrophil elastase is a host defense mechanism that causes tissue damage and reduces host tolerance to infection.
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