Defining the molecular basis of H7 flagellin as an adhesin and mucosal adjuvant for vaccine development

定义 H7 鞭毛蛋白作为疫苗开发的粘附素和粘膜佐剂的分子基础

• 批准号: BB/I011625/1
• 负责人: David Gally
• 金额: $ 33.07万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI011625%2F1
• 关键词: Defining; molecular; basis; H7; flagellin

Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 are bacteria that cause serious gastrointestinal disease in humans. Toxins released by the bacteria cause life-threatening damage to the kidneys and brain. Cattle are the main reservoir host for the bacteria and humans become infected initially by ingesting food or drink that has been contaminated, directly or indirectly, from animal faeces. One way to guard against human infection with EHEC O157 is to block or limit shedding of the organism from cattle. This can be done via vaccination of cattle. Our previous research has demonstrated that the whip-like 'flagella' of EHEC O157 that are usually used for bacterial movement, can bind to the intestinal lining of cattle to promote colonisation. If we vaccinate cattle with purified flagella, specific antibodies are generated in the gut that block this binding and limit bacterial colonisation. However, a subset of these antibodies have a negative impact in that they bind to a region of the flagella that interferes with how the host recognizes and responds to the real infection when it occurs. There are two main aims of the research. The first is to define the specific region within the flagellin molecule required for flagella binding and to use this in a vaccine preparation to study how it limits colonisation of cattle by EHEC O157. It is anticipated that by using only the region of flagellin required for binding in the gastrointestinal tract of cattle or by altering recognition of the region that stimulates inflammatory responses in mammals, we should be able to produce an effective vaccine containing flagellin that significantly reduces EHEC O157 shedding from cattle. The second part of the research is to understand how the vaccination of cattle with whole flagellin stimulates such a good antibody response on the surface of the animals gastrointestinal tract and then exploit this understanding to generate responses to other molecules linked to flagellin. Finding ways to stimulate this 'mucosal' immunity is important for the development of vaccines to many infectious diseases.

肠出血性大肠杆菌（EHEC）O157：H7是一种可引起人类严重胃肠道疾病的细菌。细菌释放的毒素会对肾脏和大脑造成危及生命的损害。牛是这种细菌的主要储存宿主，人类最初是通过直接或间接受到动物粪便污染的食物或饮料感染的。防止人类感染EHEC O157的一种方法是阻止或限制该生物体从牛身上脱落。这可以通过对牛进行疫苗接种来实现。我们之前的研究已经证明，肠出血性大肠杆菌O157的鞭状“鞭毛”通常用于细菌运动，可以结合到牛的肠道内壁，以促进定植。如果我们用纯化的鞭毛给牛接种疫苗，肠道中就会产生特异性抗体，阻止这种结合并限制细菌定植。然而，这些抗体的一个子集具有负面影响，因为它们结合鞭毛的一个区域，该区域干扰宿主在发生真实的感染时如何识别和响应。本研究有两个主要目的。首先是确定鞭毛结合所需的鞭毛蛋白分子内的特定区域，并将其用于疫苗制备中，以研究它如何限制EHEC O157在牛中的定殖。预计通过仅使用牛胃肠道中结合所需的鞭毛蛋白区域或通过改变刺激哺乳动物炎症反应的区域的识别，我们应该能够生产含有鞭毛蛋白的有效疫苗，该疫苗显著减少EHEC O157从牛的脱落。研究的第二部分是了解用全鞭毛蛋白接种牛如何在动物胃肠道表面刺激如此良好的抗体反应，然后利用这种理解来产生对与鞭毛蛋白相关的其他分子的反应。找到刺激这种“粘膜”免疫的方法对于许多传染病疫苗的开发非常重要。

项目成果

Bacterial flagella: twist and stick, or dodge across the kingdoms.

• DOI: 10.1371/journal.ppat.1004483
• 发表时间: 2015-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Rossez Y;Wolfson EB;Holmes A;Gally DL;Holden NJ
• 通讯作者: Holden NJ

Identification of epitopes recognised by mucosal CD4(+) T-cell populations from cattle experimentally colonised with Escherichia coli O157:H7.

• DOI: 10.1186/s13567-016-0374-5
• 发表时间: 2016-09-02
• 期刊: Veterinary research
• 影响因子: 4.4
• 作者: Corbishley A;Connelley TK;Wolfson EB;Ballingall K;Beckett AE;Gally DL;McNeilly TN
• 通讯作者: McNeilly TN

Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides.

大肠杆菌O157对特异性酮醇的型III型分泌依赖性敏感性。

• DOI: 10.1128/aac.02085-15
• 发表时间: 2016-01
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Fernandez-Brando RJ;Yamaguchi N;Tahoun A;McAteer SP;Gillespie T;Wang D;Argyle SA;Palermo MS;Gally DL
• 通讯作者: Gally DL

Optimizing the Protection of Cattle against Escherichia coli O157:H7 Colonization through Immunization with Different Combinations of H7 Flagellin, Tir, Intimin-531 or EspA.

• DOI: 10.1371/journal.pone.0128391
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: McNeilly TN;Mitchell MC;Corbishley A;Nath M;Simmonds H;McAteer SP;Mahajan A;Low JC;Smith DG;Huntley JF;Gally DL
• 通讯作者: Gally DL

MOESM4 of Identification of epitopes recognised by mucosal CD4+ T-cell populations from cattle experimentally colonised with Escherichia coli O157:H7

MOESM4 鉴定被大肠杆菌 O157:H7 实验定植的牛的粘膜 CD4 T 细胞群识别的表位

• DOI: 10.6084/m9.figshare.c.3642758_d5
• 发表时间: 2016
• 作者: Corbishley A