Epigenetic regulation in bacterial infections: targeting histone deacetylases.
Epigenetic regulation in bacterial infections: targeting histone deacetylases.
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DOI：
10.1080/1040841x.2017.1373063
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发表时间：
2018-05
影响因子：
6.5
通讯作者：
Potempa J
中科院分区：
文献类型：
--
作者：
Grabiec AM;Potempa J
病原体已经发展出复杂的策略来逃避免疫反应，其中宿主细胞表观遗传机制的操纵发挥着重要作用。在过去的十年中，宿主细胞中组蛋白乙酰化的调节已成为细菌免疫逃避的有效策略。病原微生物的毒力因子和代谢产物改变组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）的表达和活性，通过组蛋白乙酰化标记的表观遗传变化抑制宿主防御基因的转录。鉴于 HDAC 抑制剂引入临床实践，这种病原体与宿主相互作用的新途径尤其重要。目前正在付出大量努力来更好地了解 HDAC 抑制剂对病原体免疫反应质量的影响，并表征这些化合物在微生物感染中的治疗潜力。在这篇综述中，我们将讨论最近发现的细菌通过破坏宿主乙酰化系统来促进其在受感染宿主体内生存的机制，以及乙酰化调节剂（包括 HDAC 抑制剂和含溴结构域的 BET 蛋白抑制剂）对针对微生物病原体的先天免疫反应的影响。这两类实验证据的整合为针对传染病中蛋白质乙酰化的表观遗传疗法的前景提供了关键信息。传染病每年在全世界造成超过 1000 万人死亡，并且仍然是发病和死亡的主要原因之一，特别是在发展中国家。鉴于全球抗生素耐药性感染发病率不受控制地上升，加上过去 30 年来抗生素生产线几乎没有生产出新型抗生素，迫切需要制定新的细菌感染治疗策略。一种可能规避抗生素耐药性问题的方法涉及宿主导向治疗，其目的是通过增强免疫反应来促进病原体消除，特别是被病原体为了自身生存优势而破坏的宿主防御途径。虽然病原体如何通过破坏细胞内信号通路和转录因子激活来劫持细胞反应已得到充分证实，但细菌可能通过失调特定的表观遗传机制对宿主炎症反应产生颠覆性影响，这为宿主-微生物相互作用的生物学开辟了一个新领域。
Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and characterizing the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases. Infectious diseases cause more than 10 million deaths per year worldwide and remain one of the main causes of morbidity and mortality, particularly in the developing world. There is an urgent need to develop new treatment strategies for bacterial infections given the unchecked global rise in the incidence of antibiotic-resistant infections, coupled with an antibiotic pipeline that has produced few novel antibiotics in the last 30 years. One approach that could potentially circumvent the problem of antibiotic resistance involves host-directed therapy, which aims to promote pathogen elimination by boosting immune responses, in particular the host defense pathways that are subverted by pathogens for their own survival advantage. While it is well established how pathogens can hijack cellular responses through disruption of intracellular signaling pathways and transcription factor activation, the observation that bacteria may exert subversive effects on host inflammatory responses by dysregulating specific epigenetic mechanisms has opened a new area in the biology of host-microbe interactions.