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Discovery of bacterial defense and phage counter-defense strategies

细菌防御和噬菌体反防御策略的发现

基本信息

批准号：
10750038
负责人：
Kevin J Forsberg
金额：
$ 4.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750038
关键词：
Adsorption Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Bacteriophage lambda Bacteriophages Basic Science Biological Assay Biology CRISPR/Cas technology Cell Survival Data Databases Drug resistance Ecosystem Escherichia coli Evolution Genes Genetic Genome Genomic Islands Genomics Horizontal Gene Transfer Human Human Microbiome Immune Immunity Infection Knowledge Libraries Link Metagenomics Methods Modification Molecular Multi-Drug Resistance Mutation Nature Open Reading Frames Outcome Pathogenesis Phenotype Plasmids Prophages Proteins Resistance Resources Scheme Source Surveys System Techniques Testing Therapeutic Time Toxin Virulence Virulence Factors arms race conventional therapy flexibility gain of function human pathogen infectious disease treatment inhibitor insight metagenome microbial molecular array novel novel strategies pathogen receptor resistance gene response success

项目摘要

PROJECT SUMMARY Bacteria encode a diverse array of molecular systems to defend against infecting phages. In response, phages have devised many counter-defense strategies to overcome this immunity and re-establish infection. Mounting evidence suggests that most bacterial defense systems and phage counter-defenses in nature have not been identified. This is a major knowledge gap because the interplay between these systems often determines whether a phage successfully infects its bacterial host. These phage infections, in turn, have major impacts on the evolution and treatment of infectious disease. For instance, pathogenesis in bacteria often evolves due to the integration of a prophage that expresses a toxin or other virulence factor. At the same time, phages are increasingly viewed as potential therapeutics to treat bacterial infections, especially in cases where multi-drug resistance renders conventional treatments unsuccessful. Thus, it is important to better understand the natural diversity of bacterial defense and phage counter-defense systems. To meet this need, we will devise new high-throughput functional selections to find defense and counter-defense systems in microbial ecosystems and in libraries of synthesized phage open reading frames. This functional approach does not rely on sequence similarity to predict defense and counter-defense systems, so overcomes the limitations of conventional, homology-based discovery methods. This strategy, therefore, is expected to identify many new defense and counter-defense genes beyond what is known currently. It is especially valuable for examining functions encoded in phage genomes and bacterial genomic islands, as most genes from these sources are of unknown function. Since nearly all bacteria should encode anti-phage defense systems, and almost all phages will encode counter- defense strategies, we expect to make many new discoveries. Because these discoveries are predicted to be novel, we will use a combination of genetic and functional assays to describe their mechanisms of action. We will use Escherichia coli as a host for our functional selections, not only because this will allow us to construct large functional libraries, but also because virulence in this pathogen is driven by prophage-expressed toxins and because its phages are among those used most commonly to develop phage therapies. Thus, our findings will not only be broadly relevant to pathogenesis and phage therapy across bacteria, but also will yield these insights specifically in the context of this important human pathogen.

项目总结