Campylobacter phase variation and its impact on immunity and vaccine development.

弯曲杆菌相变及其对免疫和疫苗开发的影响。

基本信息

  • 批准号:
    BB/I024542/1
  • 负责人:
  • 金额:
    $ 37.28万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2012
  • 资助国家:
    英国
  • 起止时间:
    2012 至 无数据
  • 项目状态:
    已结题

项目摘要

Campylobacter is the commonest cause of bacterial food poisoning in the UK. One of the most frequent sources of infection for humans comes from eating undercooked poultry or cross contamination by uncooked meat during food preparation. The main problem is that Campylobacter can readily colonise poultry to very high levels without causing disease while ingestion of small amounts of bacteria by humans leads to severe gastroenteritis. These infections can result in complications as the bacterium interacts with the human immune system to cause irritable bowl syndrome and Guillain-Barré syndrome, which is an effect on the nerves of patients causing paralysis. Control of Campylobacter in poultry is predicted to significantly reduce human cases of infection. One route to achieve this is by vaccination. Vaccines induce antibodies to specific surface components of bacteria. These antibodies bind to the bacteria cells and interfere with the ability of these cells to colonise the bacterial hosts. Vaccines for Campylobacter are available but have a variable efficacy in preventing the bacterium from colonising chickens. One reason this approach is a problem is because Campylobacter naturally induces the production of antibodies against its surface components but these antibodies do not prevent colonisation or clear the bacteria from birds. Given that a range of antibody responses are generated, it is surprising that these adaptive immune responses do not clear the bacteria. This suggests that the bacteria must have a way of avoiding antibody-mediated control. We believe that Campylobacter can avoid antibodies by switching 'off' the expression of key surface molecules so that they are not recognised by the chicken's antibodies. These switches can occur at high frequencies in a process known as phase variation, which is widespread in bacterial species and is usually associated with surface components. In Campylobacter, phase variation is mediated by repeat sequences in the DNA of the bacteria which undergo a higher than normal frequency of mutation during replication of the bacteria and result in genes being switched 'on' or 'off'. If an antibody acts against the product of one of these phase variable genes, this generates selection for a change in the component by phase variation facilitating persistence of the Campylobacter in the birds. This process is reversible allowing the bacteria to recover the function of the gene when the antibodies dissipate. There is only a limited amount of data on how this process works when Campylobacter infects chickens. This project will identify the frequency of these switches and how the production of antibody impacts on selection of phase variants by the immune system. Specifically, we will investigate whether phase variation is involved in avoidance of antibodies during natural infections and following vaccination. We will assess some novel vaccine candidates for which we have evidence that phase variation may interfere with the effectiveness of induced antibodies and will modify some genes so they cannot switch 'off'. This data will not only be important in understanding how this pathogen survives in poultry but also in humans where the surface components play a major role in disease. The data generated in this project will aid in the development of effective vaccines to protect both animals and man against infections by this bacterium.
弯曲杆菌是英国细菌性食物中毒最常见的原因。人类最常见的感染来源之一是食用未煮熟的家禽或在食品制备过程中被未煮熟的肉类交叉污染。主要问题是弯曲杆菌可以很容易地在家禽中定植到非常高的水平而不会引起疾病,而人类摄入少量细菌会导致严重的肠胃炎。这些感染可能导致并发症,因为细菌与人体免疫系统相互作用,导致肠易激综合征和格林-巴罗综合征,这是一种对患者神经造成瘫痪的影响。在家禽中控制弯曲杆菌预计将显著减少人类感染病例。实现这一目标的一个途径是接种疫苗。疫苗诱导针对细菌特定表面成分的抗体。这些抗体与细菌细胞结合,干扰这些细胞在细菌宿主体内定植的能力。弯曲杆菌的疫苗是可用的,但在防止细菌在鸡体内定植方面效果不一。这种方法存在问题的一个原因是弯曲杆菌自然诱导产生针对其表面成分的抗体,但这些抗体不能阻止定植或清除鸟类体内的细菌。鉴于产生了一系列抗体反应,令人惊讶的是,这些适应性免疫反应并没有清除细菌。这表明这种细菌一定有一种避免抗体介导控制的方法。我们认为弯曲杆菌可以通过“关闭”关键表面分子的表达来避免抗体,这样它们就不会被鸡的抗体识别。这些开关可以在称为相位变化的过程中以高频率发生,这在细菌物种中很普遍,通常与表面成分有关。在弯曲杆菌中,阶段变化是由细菌DNA中的重复序列介导的,这些序列在细菌复制期间经历比正常频率更高的突变,导致基因被“打开”或“关闭”。如果抗体对这些相变基因的产物起作用,这就产生了通过相变来改变成分的选择,从而促进弯曲杆菌在鸟类中的持久性。这个过程是可逆的,当抗体消失时,细菌可以恢复基因的功能。当弯曲杆菌感染鸡时,关于这一过程如何起作用的数据有限。该项目将确定这些开关的频率,以及抗体的产生如何影响免疫系统对相变体的选择。具体来说,我们将研究在自然感染和接种疫苗后,阶段变化是否参与了抗体的避免。我们将评估一些新的候选疫苗,我们有证据表明,阶段变化可能会干扰诱导抗体的有效性,并将修改一些基因,使它们无法“关闭”。这些数据不仅对了解这种病原体如何在家禽中存活很重要,而且对了解其表面成分在疾病中起主要作用的人类也很重要。在这个项目中产生的数据将有助于开发有效的疫苗,以保护动物和人类免受这种细菌的感染。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nonselective Bottlenecks Control the Divergence and Diversification of Phase-Variable Bacterial Populations.
  • DOI:
    10.1128/mbio.02311-16
  • 发表时间:
    2017-04-04
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Aidley J;Rajopadhye S;Akinyemi NM;Lango-Scholey L;Jones MA;Bayliss CD
  • 通讯作者:
    Bayliss CD
Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization.
  • DOI:
    10.1093/nar/gks246
  • 发表时间:
    2012-07
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Bayliss CD;Bidmos FA;Anjum A;Manchev VT;Richards RL;Grossier JP;Wooldridge KG;Ketley JM;Barrow PA;Jones MA;Tretyakov MV
  • 通讯作者:
    Tretyakov MV
High Throughput Method for Analysis of Repeat Number for 28 Phase Variable Loci of Campylobacter jejuni Strain NCTC11168.
  • DOI:
    10.1371/journal.pone.0159634
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Lango-Scholey L;Aidley J;Woodacre A;Jones MA;Bayliss CD
  • 通讯作者:
    Bayliss CD
Erratum for Aidley et al., "Nonselective Bottlenecks Control the Divergence and Diversification of Phase-Variable Bacterial Populations".
  • DOI:
    10.1128/mbio.00878-17
  • 发表时间:
    2017-08-08
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Aidley J;Rajopadhye S;Akinyemi NM;Lango-Scholey L;Jones MA;Bayliss CD
  • 通讯作者:
    Bayliss CD
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Michael Jones其他文献

The Deep Determinants of Health and Education: Institutions versus Geography
健康和教育的深层决定因素:制度与地理
  • DOI:
    10.1057/9780230389946_8
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael Jones;S. Knowles;P. Owen
  • 通讯作者:
    P. Owen
Using AFS As A Distributed File System For Computational And Data Grids In High Energy Physics
使用 AFS 作为高能物理计算和数据网格的分布式文件系统
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael Jones
  • 通讯作者:
    Michael Jones
The dependence of stellar properties on initial cloud density
恒星特性对初始云密度的依赖性
Interactive Launch of 16,000 Microsoft Windows Instances on a Supercomputer
在超级计算机上交互式启动 16,000 个 Microsoft Windows 实例
  • DOI:
    10.1109/hpec.2018.8547782
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael Jones;J. Kepner;B. Orchard;A. Reuther;W. Arcand;David Bestor;Bill Bergeron;C. Byun;V. Gadepally;Michael Houle;M. Hubbell;Anna Klein;Lauren Milechin;J. Mullen;Andrew Prout;Antonio Rosa;S. Samsi;Charles Yee;P. Michaleas
  • 通讯作者:
    P. Michaleas
Looking Back to See Ahead: Unanticipated Changes in Immigration from 1986 to the Present and Their Implications for American Politics Today
回顾过去,展望未来:从 1986 年到现在意想不到的移民变化及其对当今美国政治的影响
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael Jones;E. D. Graauw
  • 通讯作者:
    E. D. Graauw

Michael Jones的其他文献

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{{ truncateString('Michael Jones', 18)}}的其他基金

SKA Mid Band 5
SKA 中频段 5
  • 批准号:
    ST/Y005376/1
  • 财政年份:
    2023
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
Collaborative Research: CompCog: Modeling Search within the Mental Lexicon
合作研究:CompCog:心理词典中的建模搜索
  • 批准号:
    2235363
  • 财政年份:
    2023
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Standard Grant
SBIR Phase I: Hermetic, Expeditionary Sailing Vessel
SBIR 第一阶段:密封式远征帆船
  • 批准号:
    2126527
  • 财政年份:
    2022
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Standard Grant
UK SKA Band 5
英国 SKA 频段 5
  • 批准号:
    ST/X001679/1
  • 财政年份:
    2022
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
Radio astronomy signal processing techniques for phased array ground
相控阵地面射电天文信号处理技术
  • 批准号:
    ST/V001329/1
  • 财政年份:
    2020
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
Square Kilometre Array: Towards Construction
平方公里阵列:走向建设
  • 批准号:
    ST/T000570/1
  • 财政年份:
    2019
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
SKA Preconstruction 2017-18
SKA 预建 2017-18
  • 批准号:
    ST/R000557/1
  • 财政年份:
    2017
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
SKA Preconstruction update
SKA 施工前更新
  • 批准号:
    ST/P005446/1
  • 财政年份:
    2016
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
SKA preconstruction funding supplement
SKA前期资金补充
  • 批准号:
    ST/N003713/1
  • 财政年份:
    2015
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant
SKA supplementary funds
SKA补充资金
  • 批准号:
    ST/M003922/1
  • 财政年份:
    2014
  • 资助金额:
    $ 37.28万
  • 项目类别:
    Research Grant

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