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构成了重大威胁，最近的例子包括艾滋病毒、非典型肺炎和埃博拉病毒。新病毒不会自发产生，而是通过获得对新宿主的偏好而从现有病毒群体中产生。然而，人们对这种现象发生的机制仍然知之甚少，而且病毒宿主偏好的变化也不容易预测。噬菌体代表了解决病毒宿主范围进化问题的强大模型系统。噬菌体种群庞大、动态且古老，它们在环境碳周转和细菌致病性中发挥着关键作用。噬菌体研究提供了多种好处，包括生物技术工具、细菌感染诊断、噬菌体治疗、合成生物学、微生物计算机和微生物电池。噬菌体群体的巨大遗传多样性、新噬菌体的分离、宿主范围的操纵以及噬菌体基因分析的容易性，提供了一个易于处理的实验系统。与其细菌宿主相比，噬菌体基因组通常很小，但噬菌体基因组序列的定义远远落后于较大宿主基因组的定义。此外，噬菌体基因组中丰富的新基因表明它们代表了生物圈中最大的未开发序列库，而我们对它的开发进展缓慢。噬菌体基因组和基因的多样性可能是由宿主与其感染病毒之间长达 3-40 亿年的战争驱动的，其中持续存在抗性宿主的压力，以及噬菌体共同进化以获取新宿主。因此，了解宿主偏好的作用以及特定基因在特定宿主中生长的需求，将为新病毒如何出现提供关键线索，并为解释噬菌体和细菌基因组提供背景。感染常见宿主菌株耻垢分枝杆菌 mc2155 的 800 个完全测序的噬菌体基因组的大量集合表明它们具有高度多样性。不仅不相关基因组种类繁多，而且相关基因组之间变异也很大，GC%在50-70%之间。我们认为，这种多样性是由多种可能的细菌宿主的可用性以及噬菌体改变宿主偏好的能力产生的，并且我们预测从相似环境中分离出来的其他宿主的噬菌体将表现出相似程度的多样性。为了探索病毒宿主范围进化的动态，我们将表征放线菌目的宿主噬菌体。单个噬菌体将被分离和测序，并使用有针对性的宏基因组策略更广泛地探索这些噬菌体的基因组多样性。这些噬菌体的宿主范围将被确定，并且宿主范围变体在多个宿主之间进化。将确定病毒在不同细菌宿主中生长的遗传要求，生物信息学分析将描述正选择下的基因、重组率、遗传交换的障碍以及宿主偏好的贡献。