Molecular mechanisms underlying the host range of bacteriophages infecting Shiga toxin-producing Escherichia coli strains

感染产志贺毒素大肠杆菌菌株的噬菌体宿主范围的分子机制

• 批准号: RGPIN-2019-04384
• 负责人: Niu, Dongyan
• 金额: $ 2.7万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=766028
• 关键词: Molecular; mechanisms; underlying; host; range

Bacteriophages (phages) are the most abundant entities across all habitats, and a major reservoir of genetic diversity, affecting microbial structure and ecosystem dynamics. The scope of host-viral interactions is poorly understood, although hypothetically all cellular organisms are prey to viral attack. Shiga-toxigenic Escherichia coli (STEC) are a diverse group of zoonotic pathogens, causing foodborne disease worldwide. New pathogenic serogroups keep emerging, but cattle and their environment continue to be the primary reservoir for STEC. Effective pre-harvest interventions are critical to minimize STEC contamination in the food supply chain. Endogenous phages are ubiquitous in cattle and their environment, regulating diversity of STEC via unknown mechanisms. Gaining mechanistic insights regarding how phages adapt to the cattle environment and prey on a variety of STEC is imperative to understand STEC ecology, and enhance phage biocontrol outcomes to mitigate STEC shedding in cattle. Molecular mechanisms that support phage-bacteria interactions are encoded in phage and host genomes. The long-term objectives of my research program are to understand how environmental phage genomes change and co-evolve with bacteria and how this shapes bacterial community structures and populations. Using a combination of approaches, including genomics, bioinformatics, genome-fitness assays and synthetic biology, my research program examines gene variety and specialization of phages and associated linkage to STEC recognition and infectivity. Availability of >70 STEC phages across 3 families enable us to address various key questions in their interactome with their host. We will determine how phage tail genes are diversified and patterned in response to divergent STEC surface structure. We will also genetically identify STEC surface structures involved in phage binding. For broad host-range phages, we will explore whether they can recognize and attach to conserved host surface structures to initiate infection. Finally, we will use genome editing to modify phage tail genes in an attempt to alter their host specificity. The proposed program is the first to systematically investigate initial interplays between various genotypes of phages and diverse serogroups of STEC, generating new knowledge on molecular mechanisms underlying host recognition and infection of STEC phages. Addressing these research objectives should greatly improve understanding of how phage genomes adapt in response to natural environments and how these changes promote adaptation and specialization in new environments. In addition, the proposed program aims to address Canada's urgent food safety challenges of pathogenic E. coli by elucidating fundamental knowledge at the primary-production level. This program will generate well trained HQP specialized in phage biology and proficient in cutting-edge technologies and other essential skills, enabling them to excel in academia, industry and elsewhere.

噬菌体（噬菌体）是所有栖息地中最丰富的实体，也是遗传多样性的主要水库，影响了微生物结构和生态系统动力学。宿主 - 病毒相互作用的范围知之甚少，尽管假设所有细胞生物都是病毒攻击的猎物。 Shiga-toxigenic Escherichia Coli（STEC）是一组多样的人畜共患病原体，在全球范围内引起食源性疾病。新的致病血清群不断出现，但牛及其环境仍然是STEC的主要储藏室。有效的收获前干预措施对于最大程度地减少食品供应链中的STEC污染至关重要。内源性噬菌体在牛及其环境中无处不在，通过未知机制来调节STEC的多样性。必须了解噬菌体如何适应牛环境和捕食各种STEC的机理见解，这对于了解STEC生态是必须的，并增强了噬菌体生物防治结果以减轻牛的Stec脱落。支持噬菌细菌相互作用的分子机制在噬菌体和宿主基因组中编码。我的研究计划的长期目标是了解环境噬菌体基因组如何与细菌发生变化和共同发展，以及这如何塑造细菌社区结构和人群。我的研究计划结合了包括基因组学，生物信息学，基因组拟合分析和合成生物学的方法，我的研究计划研究了基因品种和噬菌体的专业化以及与STEC识别和感染性相关的联系。 3个家庭中> 70个STEC噬菌体的可用性使我们能够在与主人的互动中解决各种关键问题。我们将确定如何响应Divergent STEC表面结构而多样化和图案化。我们还将在遗传上识别与噬菌体结合有关的STEC表面结构。对于广泛的宿主范围噬菌体，我们将探索它们是否可以识别并附着在保守的宿主表面结构上以启动感染。最后，我们将使用基因组编辑来修改噬菌体尾基因，以改变其宿主特异性。提出的程序是第一个系统地研究噬菌体各种基因型与STEC的多种血清群之间的初始相互作用，从而产生有关宿主识别和STEC噬菌体感染的分子机制的新知识。解决这些研究目标应大大提高人们对噬菌体基因组如何适应自然环境以及这些变化如何促进新环境中的适应和专业化的理解。此外，该计划旨在通过阐明主要生产水平的基本知识来应对加拿大致病大肠杆菌的紧急食品安全挑战。该计划将生成训练有素的HQP，专门研究噬菌体生物学，并精通尖端技术和其他基本技能，使他们能够在学术界，工业界和其他地方表现出色。