Investigation of the molecular basis of Salmonella Typhimurium Intestinal persistence

鼠伤寒沙门氏菌肠道持续存在的分子基础研究

• 批准号: BB/N007964/1
• 负责人: Robert Kingsley
• 金额: $ 55.76万
• 依托单位: Quadram Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN007964%2F1
• 关键词: Investigation; molecular; basis; Salmonella; Typhimurium

The bacterium Salmonella accounts for about 125 million incidents of disease worldwide each year, and nearly a million deaths. The morbidity and mortality caused by this pathogen has a significant impact on the economies of both resource rich and resource poor countries. Most cases of non-typhoidal Salmonella result from fecal contamination of food and food products. A common and therefore critical step for this is the entry of the bacterium into the food chain from livestock and poultry, the common zoonotic reservoir for this pathogen.While a large body of literature describes the mechanisms by which Salmonella establishes infection in the intestine, comparatively little is known about how Salmonella persists. Decreasing the amount of Salmonella in animals at slaughter is important to controlling Salmonella food-borne disease because it is the primary risk factor for introduction of this pathogen into the food chain destined for human consumption. Salmonella uses distinct mechanisms for initial colonisation and persistent colonisation and the latter represent novel targets for approaches to decrease the amount of Salmonella in livestock when they arrive at slaughter. However, in order to develop new approaches it is essential to first identify how Salmonella remains associated with the intestine in the face of competition from good bacteria resident in the intestine and the response by the host animal aimed at clearance of bacterial pathogens. This programme of work will identify all the genes encoded by Salmonella that are involved in the ability of this pathogen to remain in the intestine of livestock for prolonged periods. The relative importance of newly discovered persistence factors in this study and the previously described persistence factors ShdA and MisL will be determined in order to inform the optimal strategy for the design of intervention to decrease Salmonella colonisation. ShdA and MisL are found on the surface of Salmonella where they are known to interact with host proteins but exactly how this contributes to prolonged colonisation of the intestine is not known. We will determine how ShdA and MisL contribute to intestinal persistence, extending on a large body of published work. We will use a combination of an in vivo model of intestinal persistence developed by the applicant, studies on animal cells grown in the lab to determine the impact of ShdA and MisL on interaction of Salmonella with the host, and investigate how these bacterial proteins interact with proteins of the host. The outcome of this study will be a comprehensive overview of the intestinal persistence factors encoded by Salmonella and an understanding of the molecular basis of intestinal persistence mediated by ShdA and MisL. This data analyses will complement efforts by the livestock industry to devise strategies to decrease the incidence of Salmonella carriage that include farm-yard practice and the potential implementation of a vaccine against Salmonella.

沙门氏菌每年在全球造成约1.25亿起疾病事件，近100万人死亡。这种病原体造成的发病率和死亡率对资源丰富的国家和资源贫乏的国家的经济都有重大影响。大多数非伤寒沙门氏菌病例是由食物和食品的粪便污染引起的。一个常见的，因此也是关键的一步是细菌从牲畜和家禽进入食物链，这是这种病原体的常见人畜共患宿主。虽然大量文献描述了沙门氏菌在肠道中建立感染的机制，但对沙门氏菌如何持续存在知之甚少。减少屠宰时动物体内的沙门氏菌数量对控制沙门氏菌食源性疾病很重要，因为它是将这种病原体引入食物链供人类食用的主要风险因素。沙门氏菌使用不同的初始定植和持久定植机制，后者是减少牲畜在屠宰时沙门氏菌数量的方法的新目标。然而，为了开发新的方法，至关重要的是首先确定沙门氏菌如何在面对肠道内良好细菌的竞争时与肠道保持联系，以及宿主动物对清除细菌病原体的反应。这项工作计划将确定沙门氏菌编码的所有基因，这些基因与这种病原体长期留在牲畜肠道的能力有关。将确定本研究中新发现的持久性因子和先前描述的持久性因子SHDA和MISL的相对重要性，以便为减少沙门氏菌定植的干预设计提供最佳策略。SHDA和MISL发现于沙门氏菌表面，已知它们与宿主蛋白相互作用，但确切地说这如何导致肠道的长期定植尚不清楚。我们将在大量已发表的作品基础上，确定SHDA和MISL如何促进肠道持久性。我们将结合申请人开发的肠道持续存在的体内模型，在实验室培养的动物细胞上的研究，确定SHDA和MISL对沙门氏菌与宿主相互作用的影响，并研究这些细菌蛋白如何与宿主蛋白相互作用。这项研究的结果将是对沙门氏菌编码的肠道滞留因素的全面概述，并了解SHDA和MISL介导的肠道滞留的分子基础。这些数据分析将补充畜牧业为减少沙门氏菌携带率而作出的努力，其中包括农场实践和可能实施的沙门氏菌疫苗。

项目成果

Ecological niche adaptation of Salmonella Typhimurium U288 is associated with altered pathogenicity and reduced zoonotic potential.

• DOI: 10.1038/s42003-021-02013-4
• 发表时间: 2021-04-23
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Kirkwood M;Vohra P;Bawn M;Thilliez G;Pye H;Tanner J;Chintoan-Uta C;Branchu P;Petrovska L;Dallman T;Hall N;Stevens MP;Kingsley RA
• 通讯作者: Kingsley RA

Evolution of Salmonella within Hosts.

• DOI: 10.1016/j.tim.2018.06.001
• 发表时间: 2018-12
• 期刊: Trends in microbiology
• 影响因子: 15.9
• 作者: Tanner JR;Kingsley RA
• 通讯作者: Kingsley RA

Salmonella pathogenesis and host-adaptation in farmed animals.

养殖动物的沙门氏菌发病机制和宿主适应。

• DOI: 10.1016/j.mib.2021.05.013
• 发表时间: 2021
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Stevens MP

Genome Variation and Molecular Epidemiology of Salmonella enterica Serovar Typhimurium Pathovariants.

• DOI: 10.1128/iai.00079-18
• 发表时间: 2018-08
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Branchu P;Bawn M;Kingsley RA
• 通讯作者: Kingsley RA

Increased phage resistance through lysogenic conversion accompanying emergence of monophasic Salmonella Typhimurium ST34 pandemic strain.

• DOI: 10.1099/mgen.0.000897
• 发表时间: 2022-11
• 期刊: Microbial genomics
• 影响因子: 3.9
• 作者: Charity OJ;Acton L;Bawn M;Tassinari E;Thilliez G;Chattaway MA;Dallman TJ;Petrovska L;Kingsley RA
• 通讯作者: Kingsley RA