Role of host & bacterial factors in persistence of Salmonella in the bovine lymphatic system

主持人的角色

• 批准号: BB/K015524/1
• 负责人: Mark Stevens
• 金额: $ 72.4万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK015524%2F1
• 关键词: Role; host; bacterial; factors; persistence

Salmonella is a bacterium that causes severe diarrhoea in humans. Infections are often acquired via the food chain and environment from farmed animals owing to the ability of Salmonella to persist in their bodies. Around 94 million human cases and 155 thousand deaths occur worldwide each year. Cattle are a significant source of such infections, partly because Salmonella can leave the bovine gut via a branching network of vessels and nodular glands termed the lymphatic system. The lymphatic system normally helps to fight infection, however some types of Salmonella are adapted to survive in lymph nodes and evade the immune system. Removal of such lymph nodes is not possible on the scale of modern beef production as they are small, widely dispersed and hard to access. As a consequence, they are often incorporated into ground beef for human consumption. Large outbreaks due to ground beef have occurred, including by strains resistant to frontline medicines, and a need exists to devise strategies to prevent or reduce Salmonella infection in cattle. Such strategies are also required to enhance animal health as Salmonella are a significant cause of diarrhoea, blood-poisoning and abortion in cattle. The Stevens laboratory has been at the forefront of research to understand how Salmonella colonises the intestines of cattle and, in some cases, migrates around the body via the lymphatic system. We have developed a novel surgical model in which we insert tubes into the blood and lymphatic systems to capture bacteria as they migrate from the gut. This has shown that escape from lymph nodes via the lymphatic system can partly explain why some strains spread around the body, whereas others are confined to the gut or cleared. A key gap in our knowledge is how Salmonella enters the lymphatic system in the first place. Almost nothing is known about the host cell types with which Salmonella associates in the bovine gut or whether these migrate to the lymphatic system. The consequences of such interactions for Salmonella and the development of protective immune responses are unknown. Such gaps in knowledge are constraining our ability to design strategies to control infection. The Hopkins and Hope laboratories conduct world-leading research to understand the nature and consequences of interactions between infectious agents and cells of the ruminant immune system, which in turn is helping to improve vaccines for tuberculosis, Johne's disease, viruses and parasitic infections. Our proposal brings together substantial cash investment from Pfizer Animal Health and researchers with complementary expertise to:1. Understand how Salmonella enters the lymphatic system of cattle. This will involve inserting tubes into lymph vessels draining to lymph nodes at various sites in the gut of young calves and older steers. We will examine which cell types interact with Salmonella, how they respond and what happens to the bacteria. We will then ask whether such events can explain why some types of Salmonella are cleared by cattle whereas others spread around the body. The information will help us to target vaccines to relevant cell types and boost beneficial responses.2. Determine if different cattle-associated strains of Salmonella are equally able to spread through the lymphatic system. This will tell us whether vaccines or drugs must target a wide range of Salmonella strains, or focus on high-risk types.3. Identify Salmonella genes required for survival in the lymphatic system. We recently used a novel method to simultaneously survey the ability of hundreds of Salmonella mutants, each lacking a different character, to colonise the bovine gut wall. We are able to retrospectively apply this method to lymph nodes from the same animals to identify factors that influence persistence in the lymphatic system. Such factors may be suitable for inclusion into vaccines or as targets for drugs.

沙门氏菌是一种细菌，会导致人类严重的腹泻。由于沙门氏菌持续体内的能力，通常通过食物链和环境从养殖动物中获得感染。每年，全球约有9400万人病例和15.5万例死亡。牛是这种感染的重要来源，部分是因为沙门氏菌可以通过淋巴系统的血管和结节腺的分支网络离开牛肠。淋巴系统通常有助于抵抗感染，但是某些类型的沙门氏菌适应在淋巴结中生存并逃避免疫系统。在现代牛肉生产的规模上，由于它们很小，分散且难以进入，因此无法清除这种淋巴结。结果，它们通常被纳入碎牛肉供人类食用。发生了大规模爆发，发生了大量的牛肉，包括对前线药物有抵抗力的菌株，并且需要制定策略以防止或减少牛的沙门氏菌感染。还需要采取此类策略来增强动物健康，因为沙门氏菌是牛腹泻，血液毒和堕胎的重要原因。史蒂文斯实验室一直处于研究的最前沿，以了解沙门氏菌如何在牛的肠道上定植，并在某些情况下通过淋巴系统在体内迁移。我们开发了一种新型的手术模型，其中我们将管子插入血液和淋巴系统中，以捕获细菌从肠道中迁移时。这表明，通过淋巴系统从淋巴结中逃脱可以部分解释为什么某些菌株散布在体内，而其他菌株则局限于肠道或清除。我们所知的关键差距是沙门氏菌首先如何进入淋巴系统。关于沙门氏菌在牛肠道中与之相关的宿主细胞类型，或者这些是否迁移到淋巴系统的宿主细胞类型几乎一无所知。这种相互作用对沙门氏菌的后果和保护性免疫反应的发展尚不清楚。知识中的这种差距限制了我们设计控制感染的策略的能力。霍普金斯和希望实验室进行世界领先的研究，以了解反刍动物免疫系统感染剂和细胞之间相互作用的性质和后果，这反过来又有助于改善结核病，约翰·氏病，病毒和寄生虫感染的疫苗。我们的提案汇集了辉瑞动物健康的大量现金投资和具有互补专业知识的研究人员的大量现金投资至：1。了解沙门氏菌如何进入牛的淋巴系统。这将涉及将管子插入淋巴管中的淋巴管中，这些淋巴结在年轻小牛和年龄较大的肠道的各个部位排入淋巴结。我们将检查哪些细胞类型与沙门氏菌相互作用，它们的反应以及细菌发生的事情。然后，我们将询问此类事件是否可以解释为什么牛清除某些类型的沙门氏菌，而其他牛则散布在体内。这些信息将帮助我们将疫苗靶向相关的细胞类型并提高有益反应。2。确定不同牛相关的沙门氏菌菌株是否同样能够通过淋巴系统扩散。这将告诉我们是疫苗或药物是否必须针对各种沙门氏菌菌株，还是专注于高危类型3。确定淋巴系统中生存所需的沙门氏菌基因。最近，我们使用一种新颖的方法来同时调查数百个沙门氏菌突变体的能力，每个突变体缺乏不同的特征来定居牛肠壁。我们能够回顾性地将这种方法应用于来自相同动物的淋巴结，以识别影响淋巴系统持久性的因素。这些因素可能适合纳入疫苗或作为药物的靶标。

项目成果

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

Alternatives to antibiotics in a One Health context and the role genomics can play in reducing antimicrobial use.

• DOI: 10.1016/j.cmi.2020.02.028
• 发表时间: 2020-03
• 期刊: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
• 作者: J. Pollock;Alison S. Low;Rebecca E. McHugh;A. Muwonge;M. Stevens;A. Corbishley;D. Gally

MOESM1 of Nature and consequences of interactions between Salmonella enterica serovar Dublin and host cells in cattle

Nature 的 MOESM1 以及都柏林肠沙门氏菌与牛宿主细胞之间相互作用的后果

• DOI: 10.6084/m9.figshare.11272868
• 发表时间: 2019
• 作者: Prerna Vohra

Quantifying the Survival of Multiple Salmonella enterica Serovars In Vivo via Massively Parallel Whole-Genome Sequencing To Predict Zoonotic Risk.

• DOI: 10.1128/aem.02262-17
• 发表时间: 2018-02-15
• 期刊: Applied and environmental microbiology
• 影响因子: 4.4
• 作者: Vohra P;Bugarel M;Turner F;Loneragan GH;Hope JC;Hopkins J;Stevens MP
• 通讯作者: Stevens MP

Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa.

• DOI: 10.1371/journal.pntd.0003611
• 发表时间: 2015-03
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Okoro CK;Barquist L;Connor TR;Harris SR;Clare S;Stevens MP;Arends MJ;Hale C;Kane L;Pickard DJ;Hill J;Harcourt K;Parkhill J;Dougan G;Kingsley RA
• 通讯作者: Kingsley RA