Investigating the epigenetic regulation of pneumococcal virulence

研究肺炎球菌毒力的表观遗传调控

• 批准号: MR/M003078/1
• 负责人: Marco Rinaldo Oggioni
• 金额: $ 72.24万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM003078%2F1
• 关键词: Investigating; epigenetic; regulation; pneumococcal; virulence

In late winter the bacterium Streptococcus pneumoniae asymptomatically colonises the nasopharynx of up to seventy percent of children; it is also responsible for approximately 2.000.000 deaths worldwide due to complications of community acquired pneumonia. For over 80 years it has been recognized that when isolated from blood the bacterium forms opaque dome shaped colonies on solid laboratory medium whereas it forms flat transparent colonies when isolated from the nose. In general genetic regulatory events form the basis of the complex behaviour of any cell, both bacterial and eukaryotic; however no genetic differences could be identified between pneumococcal cells in the two distinct phase variable forms. Epigenetic regulatory mechanisms have in recent years been discovered to have a significant impact on bacterial cells. For the first time we have clear preliminary data that show that a phase variable epigenetic regulatory mechanism influences the capacity to colonise and cause invasive disease in this important human pathogen. The proposed project is aimed to elucidate the function of the phase variable restriction modification system responsible for this epigenetic regulation. The two main objectives instrumental to this aim are (i) to perform a molecular characterization of the mechanism by which the restriction modification system influences cell physiology and (ii) to describe the molecular mechanism by which the system recombines creating the epigenetically distinct subpopulations. Understanding and modelling the molecular nature of these processes is aimed to shed light on the intrinsic mechanisms by which a bacterium that is able to colonize asymptomatically in most children can rapidly change "behaviour" becoming one of the main human pathogens causing acute invasive disease. Such understanding is expected to be instrumental for designing improved intervention strategies both for prevention and treatment.

在冬季后期，肺炎链球菌无症状地定植在高达70%的儿童的鼻咽部;由于社区获得性肺炎的并发症，它还导致全球约2，000，000人死亡。80多年来，人们已经认识到，当从血液中分离时，细菌在固体实验室培养基上形成不透明的圆顶形菌落，而当从鼻子中分离时，它形成平坦透明的菌落。一般来说，基因调控事件形成了任何细胞（细菌和真核细胞）复杂行为的基础;然而，在两种不同的相变量形式的肺炎球菌细胞之间没有发现遗传差异。近年来发现表观遗传调控机制对细菌细胞有显著影响。这是我们第一次有明确的初步数据表明，相变量表观遗传调控机制影响了这种重要的人类病原体的定殖能力和引起侵袭性疾病的能力。该项目旨在阐明负责这种表观遗传调节的相位可变限制性修饰系统的功能。有助于实现这一目标的两个主要目标是（i）对限制性修饰系统影响细胞生理学的机制进行分子表征，以及（ii）描述系统重组产生表观遗传学不同亚群的分子机制。理解和模拟这些过程的分子性质的目的是揭示内在机制，通过这种机制，能够在大多数儿童中无症状地定殖的细菌可以迅速改变“行为”，成为导致急性侵入性疾病的主要人类病原体之一。这种了解预计将有助于设计更好的预防和治疗干预战略。

项目成果

Diurnal Differences in Intracellular Replication Within Splenic Macrophages Correlates With the Outcome of Pneumococcal Infection.

• DOI: 10.3389/fimmu.2022.907461
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Hames, Ryan G.;Jasiunaite, Zydrune;Ercoli, Giuseppe;Wanford, Joseph J.;Carreno, David;Straatman, Kornelis;Martinez-Pomares, Luisa;Yesilkaya, Hasan;Glenn, Sarah;Moxon, E. Richard;Andrew, Peter W.;Kyriacou, Charalambos P.;Oggioni, Marco R.
• 通讯作者: Oggioni, Marco R.

Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia.

• DOI: 10.1038/s41564-018-0147-1
• 发表时间: 2018-05
• 期刊: Nature microbiology
• 影响因子: 28.3
• 作者: Ercoli G;Fernandes VE;Chung WY;Wanford JJ;Thomson S;Bayliss CD;Straatman K;Crocker PR;Dennison A;Martinez-Pomares L;Andrew PW;Moxon ER;Oggioni MR
• 通讯作者: Oggioni MR

Analyzing Macrophage Infection at the Organ Level.

分析器官水平的巨噬细胞感染。

• DOI: 10.1007/978-1-0716-1900-1_22
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Hames RG

Splenic macrophages as the source of bacteraemia during pneumococcal pneumonia.

• DOI: 10.1016/j.ebiom.2021.103601
• 发表时间: 2021-10
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Carreno D;Wanford JJ;Jasiunaite Z;Hames RG;Chung WY;Dennison AR;Straatman K;Martinez-Pomares L;Pareek M;Orihuela CJ;Restrepo MI;Lim WS;Andrew PW;Moxon ER;Oggioni MR
• 通讯作者: Oggioni MR

Draft Whole-Genome Sequences of Periodontal Pathobionts Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia Contain Phase-Variable Restriction-Modification Systems.

• DOI: 10.1128/genomea.01229-17
• 发表时间: 2017-11-16
• 期刊: Genome announcements
• 作者: Haigh RD;Crawford LA;Ralph JD;Wanford JJ;Vartoukian SR;Hijazi K;Wade W;Oggioni MR
• 通讯作者: Oggioni MR