Dynamics of viral host range evolution

病毒宿主范围进化的动力学

• 批准号: 9002979
• 负责人: Graham F. Hatfull
• 金额: $ 48.22万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002979
• 关键词: Acquired Immunodeficiency Syndrome; Actinomycetales; Address; Anti-Bacterial Agents; Architecture; Bacterial Genome; Bacterial Infections; Bacteriophages; Bioinformatics; Biological; Biological Models; Biology; Biotechnology; Carbon; Collection; Computers; Data; Data Set; Diagnostic; Ebola virus; Environment; Essential Genes; Event; Evolution; Foundations; Frequencies; Gene Expression Profile; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Growth; HIV; Health; Human; Individual; Infection; Liquid substance; Mediating; Metagenomics; Modeling; Molecular Biology; Mycobacteriophages; Mycobacterium smegmatis; Pathogenesis; Pathogenicity; Pattern; Planets; Play; Population; Population Dynamics; Population Genetics; Process; Resistance; Resources; Role; Severe Acute Respiratory Syndrome; Specificity; System; Testing; Variant; Viral; Virulence; Virus; Virus Diseases; climate change; comparative genomics; genome sequencing; human disease; innovation; insight; man; microbial; mutant; novel; pathogen; preference; pressure; programs; public health relevance; science education; synthetic biology; tool; transcriptome sequencing; virology

 DESCRIPTION (provided by applicant) The emergence of new viruses impacting human health represents an important threat, with HIV, SARS and Ebola as recent examples. New viruses do not spontaneously generate, but arise from the extant viral population by acquisition of preferences for new hosts. However, the mechanisms by which this occurs remain poorly understood, and changes in the host preferences of viruses are not readily predictable. Bacteriophages represent a powerful model system for addressing questions of viral host range evolution. The phage population is vast, dynamic, and old, and they play key roles in environmental carbon turnover and bacterial pathogenicity. Phage studies provide a multitude of benefits, ranging biotechnology tools, diagnostics for bacterial infections, phage therapy, synthetic biology, microbial computers, and microbial batteries. The great genetic diversity of the phage population, the ease with which novel phages can be isolated, their host range manipulated, and their phage genes analyzed, presents a tractable experimental system. Phage genomes are typically small compared to their bacterial hosts, and yet the definition of phage genome sequences lags far behind that of their larger host genomes. Moreover, the abundance of novel genes within phage genomes shows they represent the largest unexplored reservoir of sequences in the biosphere, which we have been slow to tap. The diversity of phage genomes and genes is likely driven by 3-4 billion years of warfare between the hosts and their infecting viruses, with constant pressure for resistant hosts, and phage co- evolution to access new hosts. Thus, understanding the role of host preferences and the demands for specific genes to growth in specific hosts, will provide critical clues as to how new viruses emerge, and a context to interpreting both phage and bacterial genomes. A large collection of 800 completely sequenced phage genomes infecting a common host strain, Mycobacterium smegmatis mc2155 shows them to be highly diverse. Not only are there many types of unrelated genomes, but great variation among related genomes, and the GC% ranges from 50-70%. We propose that this diversity is generated by the availability of a diverse range of possible bacterial hosts, together with the ability of the phages to switch host preferences, and we predict that phages of other hosts that are isolated from similar environments will show similar degrees of diversity. To explore the dynamics of viral host range evolution we will characterize the phages of hosts within the Order Actinomycetales. Individual phages will be isolated and sequenced, and the genome diversity of these phages explored more broadly using targeted metagenomic strategies. The host ranges of these phages will be determined and host range variants evolved across several hosts. The genetic requirements for viral growth in different bacterial hosts will be established, and bioinformatic analyses will characterize genes under positive selection, recombination rates, the barriers to genetic exchange, and the contributions of host preferences.

 描述（由申请人提供） 影响人类健康的新病毒的出现代表了一个重要的威胁，艾滋病毒，SARS和埃博拉病毒是最近的例子。新病毒不会在赞助上产生，而是由于获得新宿主的偏好而源于额外的病毒种群。但是，发生这种情况的机制仍然很少了解，并且病毒宿主偏好的变化不容易预测。噬菌体代表了一个强大的模型系统，用于解决病毒宿主范围演变的问题。噬菌体种群庞大，动态且古老，它们在环境碳更换和细菌的致病性中起着关键作用。噬菌体研究提供了许多好处，范围内生物技术工具，细菌感染的诊断，噬菌体疗法，合成生物学，微生物计算机和微生物电池。噬菌体种群的巨大遗传多样性，可以隔离新噬菌体，操纵其宿主范围以及分析其噬菌体基因的易感性。与细菌宿主相比，噬菌体基因组通常很小，但是噬菌体基因组序列的定义远远落后于较大的宿主基因组的定义。此外，噬菌体基因组中新型基因的抽象表明它们代表了生物圈中最大的意外序列储备，我们可以缓慢攻击。噬菌体基因组和基因组的多样性可能是由宿主及其感染病毒之间的3 - 40亿年的战争驱动的，抗抗性宿主的压力持续压力，以及噬菌体共同进化以访问新宿主。这是了解宿主偏好的作用以及对特定基因在特定宿主中生长的需求，将为新病毒的出现以及解释噬菌体和细菌基因组的背景提供关键簇。大量的800个完全测序的噬菌体基因组感染了常见的宿主菌株，分枝杆菌MC2155表明它们是高度潜水员。不仅有许多类型的无关基因组，而且相关基因组之间的差异很大，而GC％范围为50-70％。我们建议，这种多样性是由于可能的细菌宿主的多样性范围以及噬菌体切换宿主偏好的能力而产生的，并且我们预测，与类似环境隔离的其他宿主的噬菌体将显示出相似的多样性程度。为了探索病毒宿主范围演化的动力学，我们将表征放线菌的阶段宿主的噬菌体。单个噬菌体将被隔离和测序，这些噬菌体的基因组多样性使用靶向的元基因组策略进行了更广泛的探索。这些噬菌体的主机范围将确定，并在几个主机上演变出宿主范围变体。将确定不同细菌宿主中病毒生长的遗传需求，生物信息学分析将在阳性选择，重组率，遗传交换的障碍以及宿主偏好的贡献下表征基因。