Human lung innate immune response to Bacillus anthracis spore infection
Human lung innate immune response to Bacillus anthracis spore infection
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DOI：
10.1128/iai.00046-07
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发表时间：
2007-08-01
影响因子：
3.1
通讯作者：
Metcalf, Jordan P.
中科院分区：
文献类型：
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作者：
Chakrabarty, Kaushik;Wu, Wenxin;Metcalf, Jordan P.
炭疽杆菌是吸入性炭疽病的病原体，在传播前通过肺部系统进入宿主。我们之前已经证明，人类肺泡巨噬细胞通过细胞信号介导的细胞因子释放参与对炭疽芽孢杆菌孢子的初始先天免疫反应。我们提出肺上皮细胞也参与针对这种病原体的先天免疫反应，并且我们开发了人类肺切片模型来研究这一过程。将我们的模型暴露于炭疽芽孢杆菌 (Sterne) 孢子后，会迅速激活丝裂原激活的蛋白激酶信号通路 ERK、p38 和 JNK。此外，RNase 保护测定显示多种细胞因子和趋化因子 mRNA 的诱导。这一发现反映在翻译水平上，通过酶联免疫吸附测定测定，白细胞介素 6 (IL-6)、肿瘤坏死因子 α、IL-8、巨噬细胞炎症蛋白 l α/β 和单核细胞趋化蛋白 1 的蛋白峰值分别增加了 3 倍、25 倍、9 倍、34 倍和 5 倍。 UO126、SP600125 和 SB0203580 对各个途径的抑制减少了孢子对趋化因子和细胞因子的诱导，但这取决于抑制的途径以及诱导的细胞因子和趋化因子。组合所有三种抑制剂可将所有测试的细胞因子和趋化因子的诱导降低至背景水平。 IL-6和IL-8的免疫组织化学分析表明，肺泡上皮细胞和巨噬细胞以及少数间质细胞是细胞因子和趋化因子的来源。总而言之，这些数据显示肺上皮对炭疽芽孢杆菌孢子暴露的反应而激活。因此，肺上皮通过细胞信号介导的细胞因子和趋化因子的表达，积极参与对炭疽杆菌感染的先天免疫反应。
Bacillus anthracis, the causative agent of inhalational anthrax, enters a host through the pulmonary system before dissemination. We have previously shown that human alveolar macrophages participate in the initial innate immune response to B. anthracis spores through cell signal-mediated cytokine release. We proposed that the lung epithelia also participate in the innate immune response to this pathogen, and we have developed a human lung slice model to study this process. Exposure of our model to B. anthracis (Sterne) spores rapidly activated the mitogen-activated protein kinase signaling pathways ERK, p38, and JNK. In addition, an RNase protection assay showed induction of mRNA of several cytokines and chemokines. This finding was reflected at the translational level by protein peak increases of 3-, 25-, 9-, 34-, and 5-fold for interleukin-6 (IL-6), tumor necrosis factor alpha, IL-8, macrophage inflammatory protein l alpha/beta, and monocyte chemoattractant protein 1, respectively, as determined by an enzyme-linked immunosorbent assay. Inhibition of individual pathways by UO126, SP600125, and SB0203580 decreased induction of chemokines and cytokines by spores, but this depended on the pathways inhibited and the cytokines and chemokines induced. Combining all three inhibitors reduced induction of all cytokines and chemokines tested to background levels. An immunohistochemistry analysis of IL-6 and IL-8 revealed that alveolar epithelial cells and macrophages and a few interstitial cells are the source of the cytokines and chemokines. Taken together, these data showed the activation of the pulmonary epithelium in response to B. anthracis spore exposure. Thus, the lung epithelia actively participate in the innate immune response to B. anthracis infection through cell signal-mediated elaboration of cytokines and chemokines.