Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae

霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制

• 批准号: 10033684
• 负责人: Kimberley Diane Seed
• 金额: $ 61.28万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033684
• 关键词: Address; Automobile Driving; Back; Bacterial Antibiotic Resistance; Bacteriophages; Bangladesh; Biochemical; Biological Assay; Biological Models; Cause of Death; Cholera; Collection; Conflict (Psychology); Dangerousness; Depressed mood; Development; Disease; Dysentery; Elements; Epidemic; Evolution; Extinction (Psychology); Genetic; Genetic Recombination; Genome; Genomic Instability; Genomics; Genotype; Geography; Goals; Human; In Vitro; Incidence; Infection; Infection Control; Integrase; Intestines; Island; Knowledge; Laboratories; Left; Life; Link; Measures; Mediating; Mobile Genetic Elements; Molecular; Monitor; Natural Disasters; Organism; Parasites; Patients; Pattern; Population; Positioning Attribute; Predatory Behavior; Predisposition; Production; Public Health; Race; Replication Origin; Resources; Role; Shapes; Source; Study models; System; Testing; Therapeutic; Therapeutic community technique; Time; Variant; Vibrio cholerae; Viral; Virus; Work; arm; diarrheal disease; driving force; human disease; in vivo; insight; microbial; novel; nuclease; pandemic disease; pathogen; pathogenic bacteria; prophylactic; socioeconomics; stool sample; transmission process

Illness and death caused by infectious diarrheal disease agents, like Vibrio cholerae, are major threats to public health and significant barriers to socioeconomic development worldwide. Natural disasters and continuing conflict in some depressed regions threaten to exacerbate the already rising incidence of cholera globally. As the focus of several elegant studies documenting genomic changes in epidemic strains over the last century, V. cholerae has become a well-studied model for pathogen evolution. Despite this, the mechanisms and driving forces underlying historical and current changes are not yet understood. The arms race between viruses and their host organisms is a key driving force in the evolution of all cellular life. Indeed V. cholerae must defend against the ubiquitous threat of predatory phages in aquatic reservoirs and in the intestinal tract during disease in humans. Our laboratory has shown that V. cholerae has evolved to use PLEs to defend against the predominant predatory phage ICP1. PLEs are parasitic mobile genetic elements that completely abolish ICP1 production while exploiting phage resources to further their own spread. Therefore, PLEs can be viewed both as defense systems for V. cholerae, and as phage satellites that exploit ICP1 for their own mobilization. A significant hallmark of V. cholerae PLEs is that previously prevalent PLEs disappear globally when new variants emerge, indicating that each variant is selected by unknown factors over time. However, we do not understand why such changes occur, and how new variants come to dominate over earlier prevalent variants. We hypothesize that antagonism with ICP1 and other mobile genetic elements in V. cholerae has driven the successive evolution of PLEs. We also hypothesize that reciprocal adaptations in PLE to counter those attacks have contributed to the hallmark pattern of variant extinction and replacement. To dissect the mechanisms of successive evolution of PLEs we will pursue the following specific aims: 1) We will determine how ICP1 antagonism selected for PLE variants with alternative replication modules. 2) We will define how PLE 2 mobilization renders it susceptible to ICP1 antagonism. 3) We will determine how an interfering defense island antagonizes ICP1 and PLE activity. 4) We will investigate PLE-PLE competition and the potential for recombination as a driver of PLE evolution. The proposed studies will provide insight into how epidemic V. cholerae is selected for over time and will aid in tracking the dissemination of epidemic strains. This knowledge will further enhance our understanding of phage-mediated perturbations to microbial populations in healthy and diseased states, and advance our ability to manipulate these communities for therapeutic or prophylactic benefit.

由霍乱弧菌等传染性腹泻病原体引起的疾病和死亡是对人类健康的主要威胁