Dynamics of viral host range evolution

病毒宿主范围进化的动力学

• 批准号: 9893417
• 负责人: Graham F. Hatfull
• 金额: $ 4.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893417
• 关键词: Actinobacteria class; Address; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Physiology; Bacteriophages; Bioinformatics; Biological; Biotechnology; Centrifugation; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Development; Disease; Environment; Evolution; Gene Expression Regulation; Genes; Genetic; Genome; Genome engineering; Health; Human; Infection; Intervention; Modification; Molecular Biology; Mutate; Planets; Play; Population; Prophages; Public Health; Reproduction; Resistance; Resources; Risk; Role; Specificity; Speed; System; Therapeutic; Toxin; Tuberculosis; Viral; Virus Diseases; antimicrobial drug; cystic fibrosis infection; cystic fibrosis patients; dynamical evolution; fighting; global health; innovation; microbial community; novel diagnostics; novel therapeutic intervention; 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。噬菌体数量巨大 动态的，每隔几天通过感染和繁殖进行自我更换，数量可能超过三十亿 岁了。毫不奇怪，它们在遗传上具有巨大的多样性，尽管这种多样性仍然不明确 并且只有极小部分噬菌体群体经过基因组探索。 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 通过编码毒素与许多细菌性疾病有关，并调节多种细菌生理学 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，其中存在 细菌在病毒感染的持续攻击下生存的巨大选择压力，以及 噬菌体通过突变来感染新的细菌宿主或进化出反防御系统来共同进化 克服阻力。细菌用来抵抗噬菌体感染的防御系统包括限制- 修饰和 CRISPR-Cas 系统，两者都在生物技术和生物技术领域发挥了革命性的作用 基因组工程。这些的巨大影响部分源于其非凡的效率和 特异性，三十亿年高度动态进化的结果。 细菌病原体广泛存在的抗生素耐药性这一日益严重的问题在全球范围内造成了巨大的影响。 健康风险。解决这个问题需要新的治疗方法的创新策略，以及积极的 寻找新的抗菌药物。噬菌体疗法的前景备受期待 近 100 年来，但尚未在美国广泛使用。由门内病原体引起的疾病 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问题 挑战，但治疗性噬菌体干预的任何前景都需要了解 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。 感染放线菌宿主的超过 13,000 个噬菌体的大量集合，其中 2,500 个完全被 测序，为研究噬菌体多样性、噬菌体基因组进化、噬菌体宿主提供强大的资源 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 这些噬菌体是温和的，编码表达原噬菌体并抑制噬菌体的防御系统。 不同（即异型）噬菌体对溶原菌的感染。这些防御系统多种多样，而且大多数 的基因不具有生物信息学预测的功能。防御通常是特定于某些子集的 噬菌体，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噬菌体的开发 细菌感染的新诊断、预防和治疗方法。

项目成果

Complete Genome Sequences of 61 Mycobacteriophages.

• DOI: 10.1128/genomea.00389-16
• 发表时间: 2016-07-07
• 期刊: Genome announcements
• 作者: Hatfull GF;Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) Program;KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) Mycobacterial Genetics Course;University of California–Los Angeles Research Immersion Laboratory in Virology;Phage Hunters Integrating Research and Education (PHIRE) Program
• 通讯作者: Phage Hunters Integrating Research and Education (PHIRE) Program

Genome Sequence of Gordonia Bacteriophage Lucky10.

Gordonia 噬菌体 Lucky10 的基因组序列。

• DOI: 10.1128/genomea.00580-16
• 发表时间: 2016
• 期刊: Genome announcements
• 作者: Pope,WelkinH;Brown,AleksK;Fisher,DanielJ;Okwiya,NicholasH;Savage,KaitlynA;German,BrianA;McDonnell,JillE;Schafer,ClaireE;Yu,VictorJ;Furbee,EmilyC;Grubb,SarahR;Warner,MarcieH;Montgomery,MatthewT;Garlena,RebeccaA;Rus
• 通讯作者: Rus

Genetic Manipulation of Lytic Bacteriophages with BRED: Bacteriophage Recombineering of Electroporated DNA.

使用 BRED 对裂解性噬菌体进行基因操作：电穿孔 DNA 的噬菌体重组工程。

• DOI: 10.1007/978-1-4939-8940-9_6
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Marinelli,LauraJ;Piuri,Mariana;Hatfull,GrahamF
• 通讯作者: Hatfull,GrahamF

Genome Sequences of Three Microbacterium Phages Isolated from Flowers.

从花中分离出的三种微杆菌噬菌体的基因组序列。

• DOI: 10.1128/mra.01468-18
• 发表时间: 2019
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Iles,KerryS;Zack,KiraM;Betsko,AlyssaJ;Garlena,RebeccaA;Russell,DanielA;Fetters,Andrea;Jacobs-Sera,Deborah;Ashman,Tia-Lynn;Hatfull,GrahamF
• 通讯作者: Hatfull,GrahamF

Genome Sequences of 12 Cluster AN Arthrobacter Phages.

12 簇 AN 节杆菌噬菌体的基因组序列。

• DOI: 10.1128/genomea.01092-17
• 发表时间: 2017
• 期刊: Genome announcements
• 作者: Lee-Soety,JuliaY;Bhatt,Shantanu;Adair,TamarahL;Bonilla,JAlfred;Klyczek,KarenK;Harrison,Melinda;SaintJoseph’sUniversitySEA-PHAGES;BaylorUniversitySEA-PHAGES;UniversityofWisconsin-RiverFallsSEA-PHAGES;CabriniUniversitySEA-PHAGE
• 通讯作者: CabriniUniversitySEA-PHAGE