Understanding Host Epigenetic changes to Salmonella Typhi Exposure and Infection in the context of a Human Challenge Model

在人类挑战模型的背景下了解伤寒沙门氏菌暴露和感染的宿主表观遗传变化

• 批准号: 1960082
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1960082
• 关键词: Understanding; Host; Epigenetic; changes; Salmonella

Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A is an important cause of morbidity and mortality. Around 21 million people per year develop enteric fever of which approximately 222,000 die, with children being most at risk. The majority of cases arise in South-Central and Southeast Asia. There are several key challenges in preventing and managing typhoid infection including: difficulties in diagnosing enteric fever as current tests have poor sensitivity; short term vaccine efficacy, with no licensed vaccine for children under two years old; and the emergence of antibiotic resistant strains. Novel biomarkers of infection, more efficacious vaccines and novel anti-typhoid therapies are therefore needed; achieving these goals requires a better understanding of immune response to typhoid and in particular the role of innate and adaptive cellular immunity.Enteric fever challenge studies, in which adults are challenged with a dose of typhoid bacteria with an attack rate of 65% in non-immune participants are currently being employed in Oxford to study immunity to these Salmonellae. Preliminary data show that infection, and vaccination alters gene expression in leukocytes and that these changes are associated with both immune responses and the inflammatory response during disease. How and why this occurs is governed by epigenetic mechanisms including DNA methylation and miR expression. MicroRNAs are a species of short non-coding RNA that post transcriptionally regulate 60% of genes. They are important mediators of host response to infection. MiRs are implicated in immune response e.g. miR-155 promotes an antimicrobial response by suppressing SOCS1 (suppression of cytokine signalling 1)to promote leukocyte secretion of pro-inflammatory cytokines4. MicroRNAs regulate differentiation and activation of B-cells, T-cells, monocytes and dendritic cells and therefore may govern host susceptibility to typhoid5-7. Typhoid challenge studies present the opportunity to delineate immune response to a bacterial pathogen, at an epigenetic level, in a uniquely controlled environment. This study will use small RNA sequencing techniques and methylation chips to characterise microRNA and gene methylation changes after typhoid exposure and during typhoid infection in the PBMCs of participants of an enteric fever challenge study using stored samples. Epigenetic and pre-derived transcriptomic data will be integrated to provide an unprecedented level of detail in gene expression during exposure and infection. The functional significance of DNA methylation patterns and microRNAs will be determined using in-vitro studies. Data from this project could identify novel microRNA biomarkers of typhoid or bacterial infection, and may provide biological insights into the proteins and pathways which promote or prevent typhoid infection which could be exploited to facilitate the design of novel typhoid vaccines or anti-typhoid therapeutics.

由伤寒和甲型副伤寒沙门氏菌引起的肠道热是发病和死亡的重要原因。每年约有2 100万人患上肠热病，其中约222 000人死亡，儿童的风险最大。大多数病例发生在中南亚和东南亚。在预防和管理伤寒感染方面存在几个关键挑战，包括：由于目前的测试灵敏度差，难以诊断肠热病;疫苗效力短期，没有针对两岁以下儿童的许可疫苗;以及抗生素耐药菌株的出现。因此，需要新的感染生物标志物、更有效的疫苗和新的抗伤寒疗法;实现这些目标需要更好地理解对伤寒的免疫应答，特别是先天性和适应性细胞免疫的作用。其中成年人受到一剂伤寒杆菌的攻击，在非伤寒杆菌中的发病率为65%，免疫参与者目前正在牛津大学研究对这些鲑鱼的免疫力。初步数据显示，感染和疫苗接种改变了白细胞中的基因表达，这些变化与疾病期间的免疫反应和炎症反应有关。这是如何以及为什么发生是由表观遗传机制，包括DNA甲基化和miR表达。MicroRNA是一类短的非编码RNA，在转录后调节60%的基因。它们是宿主对感染反应的重要介质。miR参与免疫应答，例如miR-155通过抑制SOCS 1（细胞因子信号传导抑制1）促进促炎细胞因子的白细胞分泌来促进抗微生物应答4。微小RNA调节B细胞、T细胞、单核细胞和树突细胞的分化和活化，因此可能控制宿主对伤寒的易感性5 -7。伤寒攻毒研究提供了在独特的受控环境中，在表观遗传水平上描述对细菌病原体的免疫应答的机会。本研究将使用小RNA测序技术和甲基化芯片来检测伤寒暴露后和伤寒感染期间，使用储存样本进行的伤寒攻毒研究参与者PBMC中的microRNA和基因甲基化变化。将整合表观遗传学和预衍生转录组学数据，以提供暴露和感染期间基因表达的前所未有的详细信息。将使用体外研究确定DNA甲基化模式和microRNA的功能意义。来自该项目的数据可以识别伤寒或细菌感染的新型microRNA生物标志物，并可以提供促进或预防伤寒感染的蛋白质和途径的生物学见解，这些蛋白质和途径可以用于促进新型伤寒疫苗或抗伤寒疗法的设计。

项目成果

Symptom study app provides real-world data on COVID-19 vaccines.

• DOI: 10.1016/s1473-3099(21)00264-4
• 发表时间: 2021-07
• 期刊: The Lancet. Infectious diseases
• 作者: Drury RE;O'Connor D
• 通讯作者: O'Connor D

The Clinical Application of MicroRNAs in Infectious Disease.

• DOI: 10.3389/fimmu.2017.01182
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Drury RE;O'Connor D;Pollard AJ
• 通讯作者: Pollard AJ

Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine.

• DOI: 10.15252/msb.20209888
• 发表时间: 2020-11
• 期刊: Molecular systems biology
• 影响因子: 9.9
• 作者: O'Connor D;Pinto MV;Sheerin D;Tomic A;Drury RE;Channon-Wells S;Galal U;Dold C;Robinson H;Kerridge S;Plested E;Hughes H;Stockdale L;Sadarangani M;Snape MD;Rollier CS;Levin M;Pollard AJ
• 通讯作者: Pollard AJ