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Phage resistance and mobile genetic elements in Vibrio cholerae

霍乱弧菌的噬菌体抗性和移动遗传元件

基本信息

批准号：
10682489
负责人：
Kimberley Diane Seed
金额：
$ 47.65万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-27 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682489
关键词：
Area Bacterial Chromosomes Bacteriophages Biochemical Biological Models Capsid Cells Cholera Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Complex Cryoelectron Microscopy DNA biosynthesis Data Defense Mechanisms Disease Disease Outbreaks Disease Outcome Ecosystem Electron Microscopy Elements Environment Epidemic Evolution Excision Gene Expression Genes Genetic Genetic Materials Genome Genomics Goals Human Infection Infection Control Infrastructure Island Life Cycle Stages Lytic Measures Mediating Mobile Genetic Elements Modification Molecular Nature Open Reading Frames Outcome Parasites Predatory Behavior Process Production Proteomics Receptor Cell Regulation Resistance Role Sanitation Small RNA System Tail Techniques Transcript Untranslated RNA Vibrio cholerae Virion Water Work clinically relevant driving force gene product global health improved inhibitor microbial novel pathogen pathogenic bacteria response targeted nucleases transmission process waterborne pathogen

项目摘要

Waterborne pathogens like Vibrio cholerae pose significant threats to global health. V. cholerae can persist in the aquatic environment, and it can emerge to cause devastating cholera outbreaks in endemic regions and vulnerable areas lacking adequate water and sanitation infrastructure. The host-pathogen interactions that dictate disease outcome and cholera transmission dynamics occur in the context of a complex microbial ecosystem that includes predatory bacterial viruses (phages). Phages profoundly impact the evolution of their bacterial hosts, both through predation, which selects for hosts with defenses that overcome phage killing and through mobilization and dissemination of genetic material. Certain mobile elements called the phage satellites have evolved sophisticated mechanisms to exploit phages for their own selfish spread. Such elements interfere with the replication of the phages they parasitize, and as such, provide their cellular hosts with a means to limit phage predation. Our lab discovered PLEs (for phage-inducible chromosomal island-like elements) in V. cholerae that provide specific and robust defense against ICP1, the dominant lytic phage co-circulating with V. cholerae in cholera endemic regions. Upon infection by ICP1, PLEs excise from the V. cholerae chromosome, replicate to high copy and are assembled into virions to spread the PLE genome to new cells while concurrently abolishing phage production. PLEs are uniquely potent, highly specific, anti-phage barriers that act through multiple mechanisms to ensure that ICP1 does not propagate and spread to neighboring V. cholerae cells. However, few mechanisms of direct interference with ICP1 are known, and none are essential for PLE activity, indicating that additional mechanisms await discovery in this system. This proposal builds on our prior work defining the PLE lifecycle in response to phage infection to gain a mechanistic understanding of how PLEs execute their unusually potent anti-phage activity. Our data indicate that PLE’s most potent anti- phage inhibitors are focused on blocking virion assembly. To understand PLE activity in mechanistic detail, we will pursue the following specific aims: 1) We will define the structural composition of virions and capsid assembly intermediates for ICP1 and PLE 2) We will Interrogate the functions of three PLE-encoded ORFs that are each sufficient to inhibit phage 3) We will determine how a PLE-encoded small RNA perturbs phage gene expression. The proposed studies are expected to reveal novel mechanistic paradigms not previously documented in phage satellites or other anti-phage defense systems. The long-term coevolution of V. cholerae PLE and ICP1 serves as a powerful model system to understand clinically relevant phage defense mechanisms to inform phage therapy efforts and understand the forces driving the evolution of bacterial pathogens.

霍乱弧菌等水媒病原体对全球健康构成重大威胁。霍乱弧菌可以在