EDGE CMT: Predicting bacteriophage susceptibility from Escherichia coli genotype

该奖项授予加州大学伯克利分校，以支持使用细菌和噬菌体作为可处理的实验系统进行宿主-病原体相互作用的研究。细菌病毒组是寄生在微生物上的病毒的集合，是微生物群落动态、活性和适应性的关键特征。作为这些群落动态的一部分，细菌病毒（噬菌体或噬菌体）攻击非常特定的细菌宿主，就像其他病毒只感染非常特定的植物或动物一样。然而，这种特异性背后的机制被深深低估，研究主要集中在少数单个细菌-噬菌体系统上。缺乏对噬菌体特异性和细菌对不同噬菌体反应的广度的了解，限制了我们建立模型的能力，这些模型可以预测哪些噬菌体有可能感染特定的细菌菌株。该奖项支持的研究将通过利用来自数百个环境和动物宿主的数千种非模型大肠杆菌菌株的广泛收集，帮助填补这一对环境和医学上重要的细菌物种及其噬菌体的知识空白。研究人员将使用相应多样化的噬菌体集合以及高通量遗传学和测量来绘制这些细菌对感染的易感性，并创建模型来预测，考虑到一种新的大肠杆菌菌株的基因组，哪种噬菌体可能最有效地靶向它。来自代表性不足群体的研究生和博士后学员将获得该奖项的支持，研究人员将使用这些研究的数据为更大群体提供数据科学培训。这一努力的结果可能最终导致有效的生物控制选择来管理细菌种群，潜在地减少对抗菌素在广泛应用领域的使用需求，包括农业、卫生、工业过程和生物医学环境。自100年前噬菌体被发现以来，我们对噬菌体丰度、多样性、感染模式及其对水平基因转移、微生物组结构和功能特征的贡献的了解仅限于少数环境背景和单个细菌-噬菌体系统。该奖项支持的研究将创建一个机器学习驱动的实验工作流程，利用细菌菌株和相关噬菌体的自然遗传变异、可扩展的易感性测定和高通量遗传学，创建一个连接细菌基因型和噬菌体易感性表型的预测模型。研究人员将利用来自数百个水库和具有代表性的农业、医疗和环境重要物种的地理位置的非模型大肠杆菌菌株的广泛收集。研究人员将采用高通量基因组学和遗传学来获得数千种噬菌体-宿主相互作用的机制理解，这些相互作用是建立连接细菌基因型和噬菌体易感性表型的预测模型所必需的。该项目的成功将促进我们对复杂易感表型的理解，并可以开发合理的噬菌体鸡尾酒配方来治疗耐药感染，实施生物防治措施，并实现精确的微生物组工程应用。研究结果将在科学会议上发表，并发表在同行评议的期刊上。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award to the University of California-Berkeley is made to support investigations of host-pathogen interactions using bacteria and phage as a tractable experimental system. The bacterial virome, the collection of viruses that parasitize the microbes, is a critical feature of microbial community dynamics, activity and adaptation. As part of these community dynamic, bacterial viruses (bacteriophage or phages) attack exceptionally specific bacterial hosts, much like other viruses infect only very-specific plants or animals. However, the mechanisms underlying this specificity are deeply under-characterized and studies have largely focused on a handful of individual bacterium-phage systems. The lack of insights into phage specificity and the breadth of bacterial responses to different phages has limited our ability to build models that can predict which phages have the potential to infect specific bacterial strains. Research supported by this award will help to fill this knowledge gap for an environmentally and medically important species of bacteria and its phage by exploiting an extensive collection of thousands of non-model Escherichia coli (e. coli) strains originating from hundreds of environmental and animal reservoirs. The researchers will use a correspondingly diverse collection of phages alongside high-throughput genetics and measurement to map the susceptibility of these bacteria to infection and create models to predict, given the genome of a new strain of E. coli, which phage might be most effective at targeting it. Graduate students and postdoctoral trainees from under-represented groups will be supported by this award, and the researchers will use data from these studies for data science training efforts available to larger groups. Results of this effort may eventually lead to effective bio-control options to manage bacterial populations, potentially reducing the need for antimicrobial use in a wide range of application areas including agriculture, sanitation, industrial processes, and biomedical environments.Since their discovery 100 years ago, our knowledge of phage abundance, diversity, modes of infectivity and their contribution to horizontal gene transfer, microbiome structure and functional traits is limited to few environmental contexts and individual bacterium-phage systems. Research supported by this award will create a machine-learning-driven experimental workflow that exploits a natural genetic variation in bacterial strains and associated phages, scalable susceptibility assays and high throughput genetics to create a predictive model connecting bacterial genotype to phage susceptibility phenotype. The researchers will leverage an extensive collection of non-model e. coli strains originating from hundreds of reservoirs and geographic locations representative of agricultural, medical and environmentally important species. The researchers will employ high-throughput genomics and genetics to gain a mechanistic understanding of thousands of phage-host interactions necessary to build predictive models linking bacterial genotype to phage susceptibility phenotype. The success of this project will advance our understanding of complex susceptibility phenotypes and could enable development of rational phage-cocktail formulations to treat drug resistance infections, implement biocontrol measures and enable precision microbiome engineering applications. The results of the studies will be presented at scientific meetings and published in peer-reviewed journals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.