Bacteriophage diversity, dynamics, function, and exploitation

噬菌体多样性、动态、功能和利用

• 批准号: 9908115
• 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/9908115
• 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; Health; Human; Infection; Intervention; 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 infection; cystic fibrosis patients; dynamical evolution; fighting; global health; innovation; microbial; microbial community; 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.

噬菌体是地球上最多的生物学实体。噬菌体种群极为 动态，每隔几天通过感染和繁殖来代替自己，可能超过30亿 年龄。毫不奇怪，尽管这种多样性仍然不明确，但它们在遗传上却有多种多样 基因组探索了噬菌体种群的一小部分。 噬菌体在环境，人类健康和生物技术中起着突出的作用。他们是 通过编码毒素与许多细菌疾病有关，并调节各种细菌生理学 方式。它们的多样性是由高度动态的微生物社区产生的 细菌的巨大选择压力，使病毒感染的持续攻击和 通过突变以感染新的细菌宿主或不断发展的反防御系统来共同发展的噬菌体 克服抵抗力。在细菌用来抵抗噬菌体感染的防御系统中，有限 修改和CRISPR-CAS系统，两者在生物技术和 基因组工程。这些的巨大影响部分源于它们的非凡效率和 特异性，高度动态演变的三十亿年的后果。 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大量的全球 健康风险。解决此问题需要新的治疗方法的创新策略，并有一种积极的策略 搜索新的抗菌剂。已经考虑了噬菌治疗的前景 将近100年，但在美国尚未发现广泛使用。病原体引起的疾病 肠结核细菌，包括囊性纤维化患者的结核病和NTM感染，是著名的公共卫生 挑战，但是任何治疗性噬菌体干预措施的前景都需要了解 噬菌体宿主范围的决定因素以及噬菌体电阻的机理和特异性。 大量收集了13,000多个噬菌体感染了阳光细菌的宿主，其中2500个完全是 测序，提供了研究噬菌体多样性，噬菌体基因组演变，噬菌体宿主的强大资源 用于结核和NTM感染的范围，细菌渗透动力学以及遗传和临床工具。许多 这些噬菌体是温带的，并且针对预言表达并抑制的防御系统代码 通过不同（即异型）噬菌体感染溶菌素。这些防御系统高度多样，大多数 这些基因没有生物信息预测的功能。防御通常是特定于几个子集 噬菌体，但靶向机制尚不清楚。 噬菌体多样性，进化，动态和抵抗的表征将有助于发展 用于细菌感染的新诊断，预防和治疗方法。