Predicting multi-scale evolution of phage-host interactions in complex environments

预测复杂环境中噬菌体-宿主相互作用的多尺度进化

• 批准号: EP/Y030141/1
• 负责人: Diana Fusco
• 金额: $ 161.39万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY030141%2F1
• 关键词: Predicting; multi; scale; evolution; phage

This proposal aims at understanding and eventually predicting how phage-host interactions occurring at the molecular and single-cell scale shape and are shaped by the spatio-temporal dynamics of the host. My approach combines mechanistic physical modelling with tunable and reproducible experiments on bacteria and a range of different phages to characterise the direction, robustness and timescale ofviral-host coevolution in complex environment that can be heterogeneous in space and changing over time.First, we will develop a comprehensive physical model that maps phage fitness to the multi-dimensional parameter space that describes phage-host interactions, on one side, and host dynamics, on the other, with goal to identify what fitness landscapes are available to a phage-host system. We will test the predictive power of our model by running multiple evolutionary experiments on 5 well-studied phages that span across the complexity of phage biology.Second, we will apply novel gene-editing techniques recently developed in my group and state-of-the-art microfluidic experiments to our library of evolved phages to investigate the effect of specific mutations on the virus-host interactions at the single-cell level and link genotype, phenotype and fitness. The result of these experiments are meant to both validate the model, but also refine the parameterization of the phage-host interactions within the model.Finally, we will apply this experimentally validated framework to predict phage-host coevolution in two complex environments: (i) gut-on-chip devices where phage and bacteria dwell in a mucosal layer and are subject to variable flow and medium conditions, and (ii) phage phi3T in B. subtilis biofilms, different spatial scales spontaneously emerge from the collective behaviour of the cell

这一建议旨在了解并最终预测噬菌体与宿主在分子和单细胞尺度上的相互作用是如何发生的，以及如何受到宿主的时空动态的影响。我的方法将机械物理模型与细菌和一系列不同噬菌体的可调和可重复性实验相结合，以表征病毒-宿主在复杂环境中协同进化的方向性、稳健性和时间尺度。首先，我们将开发一个综合的物理模型，将噬菌体适合度映射到描述噬菌体-宿主相互作用的多维参数空间，另一方面描述宿主动力学，目标是确定什么适合噬菌体-宿主系统。我们将通过对5个研究充分的噬菌体进行多个进化实验来测试我们模型的预测能力，这些噬菌体跨越噬菌体生物学的复杂性。第二，我们将应用我的团队最近开发的新基因编辑技术和最先进的微流体实验到我们的进化噬菌体库中，以研究特定突变在单细胞水平上对病毒-宿主相互作用的影响，以及连接基因、表型和适合度的影响。最后，我们将应用这个经过实验验证的框架来预测两个复杂环境中的噬菌体-宿主的协同进化：(I)肠道上的设备，其中噬菌体和细菌居住在粘膜层中，并且受到可变的流动和介质条件的影响；(Ii)在枯草杆菌生物膜中，不同的空间尺度自发地从细胞的集体行为中产生