Dynamics of viral host range evolution

 描述(由申请人提供) 影响人类健康的新病毒的出现是一个重要的威胁，艾滋病毒、SARS和埃博拉就是最近的例子。新病毒不是自发产生的，而是通过获得对新宿主的偏好而从现有的病毒种群中产生的。然而，这种情况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一个强大的模型系统。噬菌体种群庞大、动态、老化，在环境碳周转和细菌致病中起着关键作用。噬菌体研究提供了许多好处，包括生物技术工具、细菌感染诊断、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，新噬菌体的容易分离，它们的寄主范围被操纵，以及它们的噬菌体基因被分析，提供了一个易于处理的实验系统。与细菌宿主相比，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它们更大的宿主基因组。此外，噬菌体基因组中丰富的新基因表明，它们代表着生物圈中最大的未被探索的序列储存库，而我们开发这一储存库的速度一直很慢。噬菌体基因组和基因的多样性可能是由于宿主与其感染病毒之间长达30-40亿年的战争，抵抗宿主不断受到压力，以及噬菌体共同进化以获得新宿主。因此，了解宿主偏好的作用和对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。感染一种常见宿主菌株污垢分枝杆菌mc2155的800个完全测序的噬菌体基因组的大集合表明，它们是高度多样化的。不仅有多种类型的无关基因组，而且相关基因组之间的差异很大，GC%在50%-70%之间。我们认为，这种多样性是由一系列不同的可能的细菌宿主的可用性以及噬菌体切换宿主偏好的能力产生的，我们预测，从类似环境中分离的其他宿主的噬菌体将显示出类似程度的多样性。为了探索病毒宿主范围进化的动态，我们将描述放线菌目内宿主的噬菌体。将对单个噬菌体进行分离和测序，并使用有针对性的元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，并在几个宿主上进化宿主范围变体。将建立病毒在不同宿主中生长的遗传要求，生物信息学分析将表征正选择、重组率、遗传交换障碍和宿主偏好的贡献。

 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.