Bacteriophage interactions with enteric pathogens

噬菌体与肠道病原体的相互作用

• 批准号: 10399544
• 负责人: Kristin N Parent
• 金额: $ 38.57万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399544
• 关键词: Alternative Therapies; Antibiotic Resistance; Bacterial Infections; Bacteriophages; Basic Science; Binding; Binding Proteins; Biochemistry; Biological Process; Biophysics; Cell surface; Cells; Complex; Disease; Docking; Engineering; Escherichia coli; Foundations; Gene Deletion; Genetic; Goals; Health; Human; Individual; Infection; Infection Control; Laboratories; Mediating; Membrane Proteins; Microbiological Techniques; Mission; National Institute of General Medical Sciences; Outcome; Proteins; Receptor Cell; Research; Research Personnel; Research Project Grants; Resources; Salmonella; Shigella; Structure; Therapeutic Uses; Virus; Work; combat; cost; deletion library; enteric pathogen; global health; improved; innovation; insight; novel therapeutics; protein structure; receptor; technological innovation

Project Summary How phages and viruses recognize their specific host cell receptors is not known for the vast majority of species. The long-term goal is to understand the general principles behind the structures and mechanisms that control host cell entry for bacteriophages. The objective of this proposal is to determine the structures, and mechanisms of how phages use both outer and inner membrane proteins for infection in enteric pathogens such as Shigella, E.coli and Salmonella. The central hypothesis is that there are conserved protein structures and corresponding mechanisms that govern phage entry for the majority of phage:host pairs. We predict that there are universal cell surface features that are generally required for phage entry, and also other cell surface features that may be specific to individual phage:host pairs. The rationale underlying the proposed work is that we will identify key receptor proteins in enteric pathogens that mediate phage infection, and that a better understanding of these interactions will provide physical targets for either identifying new therapies or improving existing ones. We will pursue this research using a combination of conceptual and technological innovations involving genetics, biochemistry and biophysics. These include innovations recently developed in my laboratory, as well as more established microbiological techniques. The proposed research is significant, as it will provide both structural and mechanistic insights into how phages dock to their specific hosts, a necessary step for productive infection. This work will also develop resources that will be used by other researchers. For example, the proposed work will develop widely-applicable complex transposon and single gene deletion libraries, which will greatly propel research forward in Shigella, as currently no such genetic toolkit exists. The expected outcome of this work will provide a basic understanding of how phages attach to hosts including which proteins and interactions are universally required, and which are specific to individual phage:host pairs. Additionally, we will gain an atomic level understanding of the protein:protein binding interactions and transient infection intermediate states that control infection. Atomic level details, such as how phages bind to their hosts are critical for engineering new therapeutics or enhancing existing ones.

项目摘要 噬菌体和病毒如何识别其特定的宿主细胞受体并不以绝大多数 物种。长期目标是了解结构和机制背后的一般原则 控制宿主细胞进入噬菌体。该提案的目的是确定结构，并 噬菌体如何使用外膜和内膜蛋白在肠道病原体中感染的机制 例如志贺氏菌，大肠杆菌和沙门氏菌。中心假设是有保守的蛋白质结构 以及控制大多数噬菌体噬菌体进入的相应机制：宿主对。我们预测 噬菌体进入通常需要的通用细胞表面特征，还有其他细胞表面 可能特定于单个噬菌体的功能：主机对。拟议工作的基本原理是 我们将在介导噬菌体感染的肠道病原体中鉴定关键受体蛋白，并且更好 了解这些相互作用将为识别新疗法或 改善现有的。我们将使用概念和技术的结合进行这项研究 涉及遗传学，生物化学和生物物理学的创新。这些包括最近开发的创新 我的实验室以及更既定的微生物技术。拟议的研究很重要， 因为它将提供结构性和机械见解，以了解噬菌体如何停靠其特定宿主，所以 生产感染的必要步骤。这项工作还将开发其他资源 研究人员。例如，拟议的工作将开发广泛的复杂转座子和单个 基因删除库，该库将大力推动Shigella的研究，因为目前尚无这种遗传 工具包存在。这项工作的预期结果将提供对噬菌体如何附着的基本理解 宿主包括普遍需要哪些蛋白质和相互作用，哪些是特定于个人的 噬菌体：主机对。此外，我们将获得对蛋白质的原子水平理解：蛋白质结合 相互作用和瞬态感染控制感染的中间状态。原子层的细节，例如如何 噬菌体与其宿主结合对于工程新的治疗剂或增强现有治疗剂至关重要。