Multi-layered bacterial genome defences: linking molecular mechanisms to bacteria-MGE conflicts in single cells, populations, and communities.

抗菌素耐药性（AMR）的传播是一种缓慢发展的大流行病，已被世界卫生组织确定为人类面临的十大威胁之一。质粒酶和其他MGE在AMR的传播中起着关键作用，但我们对决定MGE是否以及如何通过微生物群落传播的因素只有初步的了解。一般认为，细菌免疫系统是一个主要的决定因素，但现有的研究仅限于少数几个独立的防御系统。新的生物信息学方法的发展导致了数十种以前未知的防御机制的发现，这些防御机制通常聚集在被称为“防御岛”的基因组位点内。这表明细菌基因组防御由多个集成层组成，这些层共同作用以限制MGE感染;类似于我们自己的先天和适应性免疫系统如何共同对抗病原体感染。虽然我们的初步数据支持这一假设，但缺乏系统的研究来严格检验这一新的概念框架。我们团队成员最近的研究表明，共同发生的防御可以协同作用，提供高水平的多层防御。这是非常新颖的，并提出了许多重要的问题。例如，在细菌基因组中同时出现不同的防御组合有多常见？是什么导致了防御系统的协同或对抗作用？细菌细胞内多层防御的表达和活性是如何编排的？细菌是如何平衡强大的多层防御和吸收有益基因的需求的？我们组建了一个由世界领先的英国研究人员组成的多学科团队，以解决微生物基因组进化领域中一些最紧迫的问题。我们雄心勃勃的目标是梳理出完整的，多层次的，细菌免疫系统如何在单个分子，细胞，种群和微生物群落的水平上运作，这需要在生物信息学，分子微生物学，生物化学，数学建模，显微镜和实验进化技术方面的互补专业知识和实验能力。我们的研究计划为我们对细菌基因组进化的理解提供了一个新的层次，远远超出了生物科学知识的前沿。开创的多学科方法将改变我们对细菌免疫系统在微生物基因组进化中的作用的理解，并将提高英国生物科学的国际竞争力。这项研究福尔斯属于BBSRC的优先领域，即综合微生物组研究、对抗AMR、生物科学的系统方法和数据驱动的生物学。据我们所知，没有任何其他团队以这里提议的规模参与解决这些重要问题。

The spread of antimicrobial resistance (AMR) is a slow-moving pandemic that has been identified by the WHO as one of the top 10 threats facing humanity. Plasmids and other MGEs play a key role in the dissemination of AMR, but we have only a rudimentary understanding of the factors that determine if and how MGEs spread through microbial communities. It is generally assumed that bacterial immune systems are a major determinant, but existing studies are limited to only a few stand-alone defence systems. The development of novel bioinformatics approaches led to the discovery of dozens of formerly unknown defences, often clustered within genomic loci known as 'defence islands'. This suggests that bacterial genome defences consist of multiple integrated layers that act in concert to constrain MGE infections; analogous to how our own innate and adaptive immune systems work together to combat pathogen infections. While our preliminary data supports this hypothesis, systematic studies that rigorously examine this novel conceptual framework are lacking.Recent studies by our team members have shown that co-occurring defences can interact synergistically to provide high levels of multi-layered defence. This is extremely novel and raises many important questions. For example, how common is it for different combinations of defences to co-occur in a bacterial genome? What causes defences to interact synergistically or antagonistically? How is expression and activity of multi-layered defences orchestrated within a bacterial cell? And how do bacteria balance the need for strong multi-layered defence against the need to take up beneficial genes? We assembled a multi-disciplinary team of world-leading UK researchers to tackle some of the most pressing questions in the field of microbial genome evolution. Our ambitious goal to tease apart how complete, multi-layered, bacterial immune systems operate at the level of individual molecules, cells, populations and microbial communities requires complementary expertise and experimental capacity in bioinformatics, molecular microbiology, biochemistry, mathematical modelling, microscopy, and experimental evolution techniques. Our research program provides a new tier in our understanding of bacterial genome evolution and goes well beyond the frontiers of bioscience knowledge. The multidisciplinary approaches that are pioneered will transform our understanding of the role of bacterial immune systems in microbial genome evolution and will boost international competitiveness of UK Bioscience. This research falls in the BBSRC priority areas of integrative microbiome research, combatting AMR, systems approaches to biosciences and data driven biology. As far as we know no other team is engaged in addressing these important questions at a scale that is proposed here.