Insights into pathogen immune evasion mechanisms:: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils
Insights into pathogen immune evasion mechanisms:: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils
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DOI：
10.4049/jimmunol.174.10.6364
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
DeLeo, FR
中科院分区：
文献类型：
--
作者：
Borjesson, DL;Kobayashi, SD;DeLeo, FR
多形核白细胞(PMN或中性粒细胞)是人类天然宿主防御所必需的。然而，一些细菌病原体绕过了中性粒细胞的破坏，从而导致疾病。吞噬无浆菌是人类粒细胞无形体病的病原体，通过改变正常的宿主细胞过程，如产生活性氧(ROS)和细胞凋亡，在中性粒细胞中存活下来。为了研究嗜中性粒细胞内吞噬弧菌存活的分子基础，我们使用Affymetrix微阵列检测了吞噬弧菌感染后人PMN基因表达的整体变化。值得注意的是，与金黄色葡萄球菌的吞噬作用相比，吞噬金黄色葡萄球菌引起的宿主细胞基因调控的扰动较少。尽管吞噬假单胞菌不会引起明显的PMN ROS，但致炎基因逐渐上调，表明PMN激活延迟，而不是通常在吞噬诱导的细胞凋亡过程中观察到的致炎能力的丧失。重要的是，吞噬弧菌的摄入未能触发典型的吞噬和ROS产生之后的中性粒细胞凋亡分化程序。热致死的吞噬假单胞菌在中性粒细胞基因表达和功能方面引起了一些相似的初始变化，包括延迟正常的PMN凋亡和阻断Fas诱导的程序性细胞死亡。然而，在24小时，PMN基因转录的下调可能更依赖于活动性感染。综上所述，这些发现表明，两个单独的抗凋亡过程可能同时作用于促进细菌生存：1)吞噬革兰氏杆菌未能触发通常由细菌诱导的细胞凋亡分化程序；2)病原体表面的蛋白质或分子可以介导自发性中性粒细胞凋亡的早期延迟。
Polymorphonuclear leukocytes (PMNs or neutrophils) are essential to human innate host defense. However, some bacterial pathogens circumvent destruction by PMNs and thereby cause disease. Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, survives within PMNs in part by altering normal host cell processes, such as production of reactive oxygen species (ROS) and apoptosis. To investigate the molecular basis of A. phagocytophilum survival within neutrophils, we used Affymetrix microarrays to measure global changes in human PMN gene expression following infection with A. phagocytophilum. Notably, A. phagocytophilum uptake induced fewer perturbations in host cell gene regulation compared with phagocytosis of Staphylococcus aureus. Although ingestion of A. phagocytophilum did not elicit significant PMN ROS, proinflammatory genes were gradually up-regulated, indicating delayed PMN activation rather than loss of proinflammatory capacity normally observed during phagocytosis-induced apoptosis. Importantly, ingestion of A. phagocytophilum failed to trigger the neutrophil apoptosis differentiation program that typically follows phagocytosis and ROS production. Heat-killed A. phagocytophilum caused some similar initial alterations in neutrophil gene expression and function, which included delaying normal PMN apoptosis and blocking Fas-induced programmed cell death. However, at 24 h, down-regulation of PMN gene transcription may be more reliant on active infection. Taken together, these findings suggest two separate antiapoptotic processes may work concomitantly to promote bacterial survival: 1) uptake of A. phagocytophilum fails to trigger the apoptosis differentiation program usually induced by bacteria, and 2) a protein or molecule on the pathogen surface can mediate an early delay in spontaneous neutrophil apoptosis.