Living with uninvited guests - comparing plant and animal responses to endocytic invasions
与不速之客共处——比较植物和动物对内吞入侵的反应
基本信息
- 批准号:BB/I004629/1
- 负责人:
- 金额:$ 44.94万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2010
- 资助国家:英国
- 起止时间:2010 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Salmonella are Gram-negative bacterial pathogens capable of infecting a wide range of hosts, including humans, pigs, cows, chicken and even plants. Salmonella typhimurium is the causative agent of various human and animal diseases, reaching from enteritis to typhoid fever. According to the World Health Organisation, Salmonellosis is the most frequent food-borne disease with around 1,5 billion infections world-wide yearly. Although hygiene conditions have improved considerably, the number of Salmonella infections has increased over the last decade due to antimicrobial resistance and the ability of Salmonella to hide inside host cells. Novel approaches are needed to address this global health problem. Salmonella replicates within host cells in a membrane-bound compartment and is dependent on tolerance and resources of the host cell. To ensure survival and propagation, Salmonella therefore secretes proteins into the host cytoplasm using a type III secretion system. Some of the roles of these proteins are beginning to be revealed, in particular in modulating key host signal transduction pathways. However, to fully grasp the mechanisms of host-pathogen response, we need to take a system-wide view and determining the whole network of interactions between Salmonella proteins and the host proteins. Such deep insight will yield new approaches to target the pathogens. The identification of global networks of protein-protein interactions has been accelerated in recent years by the development of high-throughput technologies such as transcriptomics and proteomics. Here, we propose to identify protein-protein interactions and pathways as a means to understand the crosstalk between plant, animal or human hosts and Salmonella. By studying diverse hosts, we will address the following questions: How do different cells respond to bacterial invasion? To which subset of bacterial gene products are host cells exposed? Are there host 'weak points' that Salmonella exploits in animals and plant cells alike? We propose the idea that addressing these basic biological questions for divergent hosts such as plants and animals can help us elucidate the way the interaction between the host and the pathogen works at the mechanistic level. Analyzing the responses of different hosts to invasion, and integrating these results using a systems biology approach will expose the weaknesses and strengths in host responses. This will advance the field through the development of tools for the integration of data analysis, modelling and experimentation. In practical terms, this information can be exploited for drug development, diagnosis, disease forecasting, prevention and control. Our working hypothesis is that plants and animals respond to pathogen invasion in fundamentally similar ways, and that species-specificity is conferred by nuances on general themes. This means, that in principle, similar approaches should be applicable to design strategies to detect and fight Salmonella infections irrespective of host. We will test this hypothesis through an integrative cycle of computational and experimental approaches. The outcome will be either a unified model for the general host response, or separate models, one for each host. Thus, both, proving or disproving the hypothesis will be equally valuable.
沙门氏菌是一种革兰氏阴性细菌,能够感染广泛的宿主,包括人、猪、牛、鸡甚至植物。鼠伤寒沙门氏菌是多种人类和动物疾病的病原体,从肠炎到伤寒。根据世界卫生组织的数据,沙门氏菌病是最常见的食源性疾病,每年全球约有15亿人感染。尽管卫生条件有了很大改善,但由于抗菌素耐药性和沙门氏菌隐藏在宿主细胞内的能力,沙门氏菌感染的数量在过去十年中有所增加。需要新的方法来解决这一全球健康问题。沙门氏菌在宿主细胞内以膜结合的间隔进行复制,并依赖于宿主细胞的耐受性和资源。因此,为了确保生存和繁殖,沙门氏菌使用III型分泌系统将蛋白质分泌到宿主细胞质中。这些蛋白质的一些作用开始被揭示,特别是在调节关键的宿主信号转导途径方面。然而,要全面了解宿主-病原体反应的机制,我们需要从系统的角度出发,确定沙门氏菌蛋白与宿主蛋白之间的整个相互作用网络。这种深刻的洞察力将产生针对病原体的新方法。近年来,转录组学和蛋白质组学等高通量技术的发展加速了全球蛋白质相互作用网络的确定。在这里,我们建议确定蛋白质-蛋白质相互作用和途径作为一种手段,以了解植物、动物或人类宿主与沙门氏菌之间的串扰。通过研究不同的宿主,我们将解决以下问题:不同的细胞如何应对细菌入侵?宿主细胞暴露于细菌基因产物的哪个子集?沙门氏菌在动物和植物细胞中是否同样存在宿主“弱点”?我们提出的想法是,为不同的宿主(如植物和动物)解决这些基本的生物学问题,可以帮助我们从机制水平上阐明宿主和病原体之间的相互作用方式。分析不同宿主对入侵的反应,并使用系统生物学方法整合这些结果,将揭示宿主反应中的弱点和优势。这将通过开发综合数据分析、建模和实验的工具来推动该领域的发展。实际上,这些信息可用于药物开发、诊断、疾病预测、预防和控制。我们的工作假设是,植物和动物对病原体入侵的反应方式基本上相似,物种特异性是由一般主题上的细微差别授予的。这意味着,原则上,类似的方法应适用于设计战略,以检测和抗击沙门氏菌感染,而不考虑宿主。我们将通过计算和实验方法的综合循环来检验这一假设。结果将是一个通用的主机响应的统一模型,或者每个主机一个单独的模型。因此,无论是证明还是反驳这一假设,都将具有同等的价值。
项目成果
期刊论文数量(0)
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Gary Coulton其他文献
In situ hybridization comes of age
- DOI:
10.1007/bf00164166 - 发表时间:
1995-01-01 - 期刊:
- 影响因子:2.200
- 作者:
Gary Coulton - 通讯作者:
Gary Coulton
Gary Coulton的其他文献
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相似海外基金
Living with uninvited guests - comparing plant and animal responses to endocytic invasions
与不速之客共处——比较植物和动物对内吞入侵的反应
- 批准号:
BB/I004548/1 - 财政年份:2010
- 资助金额:
$ 44.94万 - 项目类别:
Research Grant