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.

沙门氏菌是一种引起人类严重腹泻的细菌。由于沙门氏菌能够在养殖动物体内持续存在，感染通常是通过食物链和环境从养殖动物身上获得的。全球每年约有 9,400 万人类病例和 15.5 万人死亡。牛是此类感染的重要来源，部分原因是沙门氏菌可以通过血管和结节腺（称为淋巴系统）的分支网络离开牛肠道。淋巴系统通常有助于抵抗感染，但某些类型的沙门氏菌适合在淋巴结中生存并逃避免疫系统。在现代牛肉生产规模上不可能切除这些淋巴结，因为它们很小、分布广泛且难以接近。因此，它们经常被掺入碎牛肉中供人类食用。由于碎牛肉引起的大规模疫情已经发生，包括对一线药物产生抗药性的菌株，因此需要制定预防或减少牛沙门氏菌感染的策略。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、血液中毒和流产的重要原因。史蒂文斯实验室一直处于研究的前沿，了解沙门氏菌如何在牛的肠道中定植，并在某些情况下通过淋巴系统在身体各处迁移。我们开发了一种新颖的手术模型，将管子插入血液和淋巴系统，以捕获从肠道迁移的细菌。这表明，通过淋巴系统从淋巴结逃逸可以部分解释为什么某些菌株在全身传播，而另一些菌株则局限于肠道或被清除。我们知识中的一个关键差距是沙门氏菌最初如何进入淋巴系统。关于牛肠道中沙门氏菌所关联的宿主细胞类型或这些细胞是否迁移到淋巴系统几乎一无所知。这种相互作用对沙门氏菌的影响以及保护性免疫反应的发展尚不清楚。这种知识差距限制了我们设计控制感染策略的能力。霍普金斯大学和霍普实验室进行了世界领先的研究，以了解感染原与反刍动物免疫系统细胞之间相互作用的性质和后果，这反过来又有助于改进结核病、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保健公司和具有互补专业知识的研究人员的大量现金投资：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，引流至幼小犊牛和年长公牛肠道不同部位的淋巴结。我们将研究哪些细胞类型与沙门氏菌相互作用、它们如何反应以及细菌会发生什么。然后我们会问这些事件是否可以解释为什么某些类型的沙门氏菌可以被牛清除，而其他类型的沙门氏菌则在全身传播。这些信息将帮助我们针对相关细胞类型开发疫苗并增强有益反应。2．确定与牛相关的不同沙门氏菌菌株是否同样能够通过淋巴系统传播。这将告诉我们疫苗或药物是否必须针对广泛的沙门氏菌菌株，或者专注于高风险类型。3。鉴定沙门氏菌在淋巴系统中生存所需的基因。我们最近使用一种新颖的方法同时调查了数百种沙门氏菌突变体（每种突变体都缺乏不同的特征）在牛肠壁上定殖的能力。我们能够回顾性地将这种方法应用于同一动物的淋巴结，以确定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点。

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