Mathematical Virology: A new mathematical approach to viral evolution grounded in experiment

数学病毒学：基于实验的病毒进化的新数学方法

• 批准号: EP/K028286/1
• 负责人: Reidun Twarock
• 金额: $ 35.48万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FK028286%2F1
• 关键词: Mathematical; Virology; new; mathematical; approach

Society faces a number of major challenges due to the impact of global warming on world climate. One consequence is the spread of otherwise rare and poorly characterised viral infections into economically advanced areas of the world. Examples include Bluetongue virus, which arrived in the UK after years of being restricted to much warmer climates. This poses a threat to public and animal health from both existing viruses and newly emerging ones. A major problem in the design of anti-viral therapies is the emergence of viral strains that are resistant to anti-viral drugs soon after initial treatment. Research into the mechanisms that could prevent such viral escape is therefore urgently required in order to develop therapeutics with long-term action. Moreover, viruses can evolve strains that cross the species barrier, for example from an animal to a human host as in the case of bird flu, and it is important to be able to develop strategies to prevent this. Insights into virus evolution could shed light on both issues. In particular, we need to better understand the constraints that viruses face when their genomes evolve, and find ways of predicting such evolutionary behaviour. In our previous research we have gained fundamentally new insights into the constraints underlying virus structure and function. In an interdisciplinary research programme, combining the modelling expertise of the Twarock group at the York Centre for Complex Systems Analysis at the University of York with the experimental know-how of the Stockley and Rowlands Labs at the Astbury Centre for Structural Molecular Biology In Leeds, we investigate here their impact on the evolution of viruses, working with a number of viruses including picornaviridae that contain important human and animal viruses, such as foot-and-mouth virus. Our research programme aims at improving our understanding of the factors that determine the evolutionary behaviour of viruses, and we will use these results to explore strategies to misdirect viral evolution. In particular, we will assess in which ways the structural constraints we have discovered earlier lead to evolutionary bottlenecks, i.e. correspond to constraints that the viral escape mutants cannot avoid, and that a new generation of anti-viral therapeutics could target. Moreover, we plan to develop methods to predict how viruses may react to a drug, and use this to test the impact of different anti-viral strategies. This research has the potential to lead to a new generation of "evolutionarily-stable" therapeutics that are less susceptible to the problem of escape mutants.

由于全球变暖对世界气候的影响，社会面临着许多重大挑战。一个后果是，原本罕见且特征不明确的病毒感染蔓延到世界经济发达地区。例子包括蓝舌病病毒，它在多年来被限制在温暖得多的气候条件下到达英国。现有病毒和新出现的病毒对公众和动物健康构成威胁。设计抗病毒治疗的一个主要问题是在初始治疗后不久出现对抗病毒药物具有耐药性的病毒株。因此，迫切需要研究能够阻止这种病毒逃逸的机制，以便开发具有长期作用的治疗方法。此外，病毒可以进化出跨越物种屏障的毒株，例如像禽流感那样从动物宿主传播到人类宿主，能够制定预防这种情况的策略是很重要的。对病毒进化的深入了解可能会对这两个问题有所帮助。特别是，我们需要更好地了解病毒基因组进化时面临的限制，并找到预测这种进化行为的方法。在我们之前的研究中，我们对病毒结构和功能背后的制约因素有了根本性的新见解。在一个跨学科的研究项目中，我们将约克大学约克复杂系统分析中心Twarock小组的建模专业知识与利兹阿斯特伯里结构分子生物学中心斯托克利和罗兰兹实验室的实验技术相结合，研究了它们对病毒进化的影响，研究了许多病毒，包括含有重要人类和动物病毒的小核糖核酸病毒科，比如口蹄疫病毒。我们的研究计划旨在提高我们对决定病毒进化行为的因素的理解，我们将利用这些结果来探索误导病毒进化的策略。特别是，我们将评估我们先前发现的结构限制以何种方式导致进化瓶颈，即对应于病毒逃逸突变体无法避免的限制，以及新一代抗病毒疗法可以针对的限制。此外，我们计划开发方法来预测病毒对药物的反应，并用它来测试不同抗病毒策略的影响。这项研究有可能导致新一代“进化稳定”的治疗方法，这种治疗方法不太容易受到逃逸突变体的影响。

项目成果

RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance.

• DOI: 10.3390/v9110347
• 发表时间: 2017-11-17
• 期刊: Viruses
• 作者: Bingham RJ;Dykeman EC;Twarock R
• 通讯作者: Twarock R

Encyclopedia of Virology

病毒学百科全书

• DOI: 10.1016/b978-0-12-814515-9.00110-7
• 发表时间: 2021
• 作者: Bingham R

Protein-mediated RNA folding governs sequence-specific interactions between rotavirus genome segments.

• DOI: 10.7554/elife.27453
• 发表时间: 2017-09-18
• 期刊: eLife
• 影响因子: 7.7
• 作者: Borodavka A;Dykeman EC;Schrimpf W;Lamb DC
• 通讯作者: Lamb DC

A multiscale model of virus pandemic: Heterogeneous interactive entities in a globally connected world.

• DOI: 10.1142/s0218202520500323
• 发表时间: 2020-07
• 期刊: Mathematical models & methods in applied sciences : M3AS
• 作者: Bellomo N;Bingham R;Chaplain MAJ;Dosi G;Forni G;Knopoff DA;Lowengrub J;Twarock R;Virgillito ME
• 通讯作者: Virgillito ME