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Epigenetic reprogramming of innate immunity during uropathogenic E. coli infection in surrogate insect model

代理昆虫模型中尿路致病性大肠杆菌感染期间先天免疫的表观遗传重编程

基本信息

批准号：
299244350
负责人：
Dr. Krishnendu Mukherjee, Ph.D.
金额：
--
依托单位：
Institut für Hygiene
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/299244350?language=en
关键词：
Epigenetic reprogramming innate immunity during

项目摘要

Pathogen infection in humans involves specific pro- and anti-inflammatory innate immune responses the transcription of which is regulated by epigenetic mechanisms such as DNA methylation and histone acetylation. Thus, epigenetic mechanisms are being increasingly considered to combat complicated infections such as in the urinary tract of humans by ExPEC. However, this requires extensive screening of strains, serotypes, and virulence factors in a whole animal high-throughput screening system which is cost effective, ethically unrestricted, with short generation times and correlates the results to humans. Insects fit to these criteria and share innate immunity and conserved epigenetic mechanisms with humans. The prime objective of the proposed project is to identify epigenetic alterations that are induced through UPEC infection in a surrogate insect host to expedite the development of epigenetic based anti-infective strategies for clinical application. UPEC and other ExPEC strains that are responsible for causing UTIs in humans impose an annual healthcare budget of over 2.5 billion dollar in the USA and Europe and can infect the greater wax moth G. mellonella at 37°C. This provides scope to explore this insect model for elucidating novel aspects of mechanisms leading to UPEC virulence and antimicrobial resistance. In addition, G. mellonella offer a number of advantages over mammalian models including the study of complex interacting parameters such as fecundity, longevity, gender ratio even at the transgenerational level. We hypothesize that UPEC infects G. mellonella by targeting epigenetic mechanisms in order to repress transcriptional activation of bactericidal host responses. This will be tested by analyzing innate immunity and epigenetic alterations induced through methylating cytosines and acetylating/ deacetylating histones following exposure to uropathogenic and non-pathogenic E. coli. The potential impact of such bacteria induced epigenetic regulations on the expression host defense molecules across generations will be investigated in G. mellonella larvae.

人类病原体感染涉及特异性的促炎性先天免疫反应，其转录受表观遗传机制（如DNA甲基化和组蛋白乙酰化）的调节。因此，表观遗传机制被越来越多地认为是对抗复杂的感染，如在人类尿路的exp。然而，这需要在全动物高通量筛选系统中广泛筛选菌株、血清型和毒力因子，这种筛选系统具有成本效益，伦理上不受限制，生成时间短，并将结果与人类相关联。昆虫符合这些标准，并与人类共享先天免疫和保守的表观遗传机制。该项目的主要目标是确定通过UPEC感染在代理昆虫宿主中诱导的表观遗传改变，以加快临床应用的基于表观遗传的抗感染策略的发展。UPEC和其他导致人类尿路感染的ExPEC菌株在美国和欧洲每年造成超过25亿美元的医疗保健预算，并且可以在37°C下感染大蜡蛾G. mellonella。这为探索这种昆虫模型提供了范围，以阐明导致UPEC毒力和抗菌素耐药性的机制的新方面。此外，与哺乳动物模型相比，mellonella提供了许多优势，包括研究繁殖力、寿命、性别比例等复杂的相互作用参数，甚至在跨代水平上。我们假设UPEC通过靶向表观遗传机制感染大黄蜂，以抑制杀菌宿主反应的转录激活。这将通过分析暴露于尿路致病性和非致病性大肠杆菌后，通过甲基化胞嘧啶和乙酰化/去乙酰化组蛋白诱导的先天免疫和表观遗传改变来验证。这些细菌诱导的表观遗传调控对宿主防御分子跨代表达的潜在影响将在大黄蜂幼虫中进行研究。