Bacteriophage diversity, dynamics, function, and exploitation

噬菌体多样性、动态、功能和利用

• 批准号: 10615099
• 负责人: Graham F. Hatfull
• 金额: $ 45.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615099
• 关键词: Actinobacteria class; Address; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Physiology; Bacteriophages; Bioinformatics; Biological; Biotechnology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Development; Disease; Environment; Evolution; Genes; Genetic; Genome; Genome engineering; Genomics; Health; Human; Infection; Intervention; Maps; Modification; Molecular; Mutate; Organism; Pathogenesis; Planets; Play; Population; Prophages; Public Health; Reproduction; Resistance; Resources; Risk; Role; Specificity; System; Therapeutic; Toxin; Tuberculosis; Virus Diseases; antimicrobial drug; cystic fibrosis patients; dynamical evolution; fighting; geochemistry; global health; innovation; microbial; microbial community; non-tuberculous mycobacterial infection; novel diagnostics; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic bacteria; pressure; tool

Bacteriophages are the most numerous biological entities on the planet. The phage population is enormously dynamic, replacing itself through infection and reproduction every few days, and may be more than three billion years old. Not surprisingly, they are enormously diverse genetically, although this diversity remains ill-defined and only an extremely small part of the phage population has been genomically explored. Bacteriophages play prominent roles in the environment, in human health, and in biotechnology. They are implicated in many bacterial diseases by coding for toxins, and modulate bacterial physiology in a variety of ways. Their diversity is generated in part by the highly dynamic microbial community in which there is enormous selective pressure for bacteria to survive the constant onslaught of viral infections, and for the phages to co-evolve by mutating to infect new bacterial hosts or evolving counter-defense systems that overcome resistance. Among the defense systems that bacteria use to fight off phage infection are restriction- modification and CRISPR-Cas systems, both of which have played revolutionary roles in biotechnology and genome engineering. The huge impact of these derives in part from their extraordinary efficiency and specificity, the consequences of three billion years of highly dynamic evolution. The growing problem of widespread antibiotic resistance by bacterial pathogens presents a substantial global health risk. Addressing this requires innovative strategies for new therapeutic approaches, and an aggressive search for new antimicrobial agents. The prospects of bacteriophage therapy have been contemplated for nearly 100 years, but has not found widespread use in the US. Diseases caused by pathogens in the phylum Actinobacteria, including tuberculosis and NTM infections of Cystic Fibrosis patients, are notable public health challenges, but any prospects for therapeutic phage interventions requires an understanding of the determinants of phage host range and the mechanisms and specificity of phage resistance. A large collection of over 13,000 phages infecting Actinobacterial hosts, 2,500 of which are completely sequenced, provide a powerful resource for investigating phage diversity, phage genome evolution, phage host range, bacterial-phage dynamics, and genetic and clinical tools for tuberculosis and NTM infections. Many of these phages are temperate, and code for defense systems that are prophage-expressed and inhibit the infection of lysogens by different (i.e. heterotypic) phages. These defense systems are highly varied and most of the genes do not have bioinformatically predicted functions. Defense is often specific for a few subset of the phages, but the mechanisms of targeting is not known. The characterization of phage diversity, evolution, dynamics, and resistance will facilitate the development of new diagnostic, preventative, and therapeutic approaches for bacterial infections.

噬菌体是地球上数量最多的生物实体。噬菌体的数量 每隔几天就通过感染和繁殖进行自我更新，数量可能超过30亿 岁毫不奇怪，他们在基因上有着巨大的多样性，尽管这种多样性仍然不明确 并且只有极少数噬菌体群体被基因组学研究。 噬菌体在环境、人类健康和生物技术中发挥着重要作用。他们是 通过编码毒素参与许多细菌性疾病，并在多种细菌中调节细菌生理学。 的方式它们的多样性部分是由高度动态的微生物群落产生的， 细菌在病毒感染的持续冲击下生存的巨大选择压力， 通过突变感染新的细菌宿主或进化出反防御系统， 克服阻力。细菌用来抵抗噬菌体感染的防御系统之一是限制性- 修饰和CRISPR-Cas系统，两者都在生物技术中发挥了革命性的作用， 基因工程它们的巨大影响部分来自于它们非凡的效率， 特异性，三十亿年高度动态进化的结果。 细菌病原体的广泛抗生素耐药性的日益严重的问题呈现出实质性的全球性问题。 健康风险。解决这一问题需要新的治疗方法的创新策略，以及积极的 寻找新的抗菌剂。噬菌体治疗的前景已被考虑， 近100年来，它一直没有在美国广泛使用。由门中病原体引起的疾病 放线菌，包括结核病和囊性纤维化患者的NTM感染，是值得注意的公共卫生 挑战，但任何治疗性噬菌体干预的前景都需要了解 噬菌体宿主范围的决定因素以及噬菌体抗性的机制和特异性。 大量收集了超过13，000种感染放线菌的宿主，其中2，500种完全 测序，为研究噬菌体多样性、噬菌体基因组进化、噬菌体宿主 范围，细菌噬菌体动力学，以及结核病和NTM感染的遗传和临床工具。许多 这些蛋白质是温和的，编码防御系统，这些防御系统是前噬菌体表达的，并抑制细胞增殖。 溶原菌被不同的（即异型的）细菌感染。这些防御系统种类繁多， 的基因不具有生物信息学预测的功能。防御往往是具体的几个子集， 但靶向机制尚不清楚。 噬菌体多样性、进化、动力学和抗性的表征将促进 新的诊断、预防和治疗细菌感染的方法。