Anaplasma phagocytophilum increases the levels of histone modifying enzymes to inhibit cell apoptosis and facilitate pathogen infection in the tick vector Ixodes scapularis
Anaplasma phagocytophilum increases the levels of histone modifying enzymes to inhibit cell apoptosis and facilitate pathogen infection in the tick vector Ixodes scapularis
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DOI：
10.1080/15592294.2016.1163460
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发表时间：
2016-01-01
期刊：
影响因子：
3.7
通讯作者：
de la Fuente, Jose
中科院分区：
文献类型：
--
作者：
Cabezas-Cruz, Alejandro;Alberdi, Pilar;de la Fuente, Jose
尽管蜱虫作为人类和动物疾病的重要载体，但其表观遗传机制尚未得到表征。本研究的目的是表征蜱媒介肩突硬蜱的组蛋白和组蛋白修饰酶（HME）及其在嗜吞噬细胞无形体感染中的作用。我们首先在I.与模式生物中的类似蛋白质比较。然后，我们使用转录组学和蛋白质组学数据分析I.肩胛肌组蛋白和HME对A.蜱组织和培养细胞的嗜吞噬细胞菌感染。最后，通过在培养的蜱细胞中进行药理学研究，对选定的HME进行功能表征。结果表明，A.嗜吞噬细胞菌操纵蜱细胞表观遗传学以增加I.肩胛肌p300/CBP、组蛋白脱乙酰酶和Sirtuin水平，导致细胞凋亡的抑制，进而促进病原体感染和增殖。这些结果还表明，A.嗜吞噬细胞菌操纵蜱HME以组织特异性方式调节转录和凋亡以促进感染，但保持蜱适应性以保证病原体和蜱的存活。我们的研究还表明，病原体操纵节肢动物和脊椎动物细胞表观遗传学以类似的方式抑制宿主对感染的反应。蜱类生物学过程的表观遗传调控是A.研究嗜吞噬细胞蜱的作用机制和主要参与者可能为抗蜱药物和疫苗的开发提供线索。
Epigenetic mechanisms have not been characterized in ticks despite their importance as vectors of human and animal diseases worldwide. The objective of this study was to characterize the histones and histone modifying enzymes (HMEs) of the tick vector Ixodes scapularis and their role during Anaplasma phagocytophilum infection. We first identified 5 histones and 34 HMEs in I. scapularis in comparison with similar proteins in model organisms. Then, we used transcriptomic and proteomic data to analyze the mRNA and protein levels of I. scapularis histones and HMEs in response to A. phagocytophilum infection of tick tissues and cultured cells. Finally, selected HMEs were functionally characterized by pharmacological studies in cultured tick cells. The results suggest that A. phagocytophilum manipulates tick cell epigenetics to increase I. scapularis p300/CBP, histone deacetylase, and Sirtuin levels, resulting in an inhibition of cell apoptosis that in turn facilitates pathogen infection and multiplication. These results also suggest that a compensatory mechanism might exist by which A. phagocytophilum manipulates tick HMEs to regulate transcription and apoptosis in a tissue-specific manner to facilitate infection, but preserving tick fitness to guarantee survival of both pathogens and ticks. Our study also indicates that the pathogen manipulates arthropod and vertebrate cell epigenetics in similar ways to inhibit the host response to infection. Epigenetic regulation of tick biological processes is an essential element of the infection by A. phagocytophilum and the study of the mechanisms and principal actors involved is likely to provide clues for the development of anti-tick drugs and vaccines.