Harnessing the potential of atypical gDNA processing by domesticated viruses

利用驯化病毒非典型 gDNA 加工的潜力

• 批准号: BB/V016288/1
• 负责人: Paul Fogg
• 金额: $ 62.08万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016288%2F1
• 关键词: Harnessing; potential; atypical; gDNA; processing; Harnessing; potential; atypical; gDNA; processing

Horizontal Gene Transfer (HGT) is a fundamental and powerful process for the exchange of genes between bacteria. HGT drives bacterial evolution, adaptation and spread into new ecological niches and is the primary means for rapid distribution of characteristics such as antibiotic resistance and pathogenicity. Viruses that infect bacteria are known as bacteriophages, or simply phages, and are generally accepted to be the most influential mechanism of HGT. Gene Transfer Agents (GTAs) are small viral particles that are related to bacteriophages and are able to indiscriminately transfer almost any gene between bacterial cells. Research into the activity of GTAs in the environment revealed that antibiotic resistance genes could be spread at extremely high frequencies and thus GTA-mediated spread of antibiotic resistance and virulence genes in pathogens has huge potential clinical and economic consequences.The overarching goal of this research project is to characterize the structure and function of the GTA DNA recognition machinery. Viruses are usually selfish elements whose main goal is to use the resources of their host to make copies of themselves that can then move on to infect new hosts. Despite being similar to traditional viruses in many ways, GTAs do not copy their own genome and do not promote their own survival at the expense of their host. Instead GTAs package the entire genome of their bacterial host in bitesize pieces and distribute these to recipient bacteria. When the species that produces GTAs contains genes for enhanced pathogenesis or antibiotic resistance, this indiscriminate gene transfer becomes of great concern. In bacteriophages, the protein that is responsible for specific recognition of the phage genome is called the small terminase. The small terminase also regulates the enzymatic activities of the large terminase protein, which cuts the target DNA and rapidly feeds it into a pre-formed empty viral head until the whole genome is packaged. Although GTA large terminases are easily identified through bioinformatics owing to classical ATP hydrolysis sequence motifs, no GTA small terminase has ever been identified.Our preliminary data provide the first evidence that a GTA possesses a small terminase and allows prediction of similar small terminases in other diverse GTAs. We will examine the biochemistry and structure of GTA small terminases, which will allow the fundamental properties of these atypical terminases to be defined with a view to increasing the efficiency of detection of novel GTAs and to provide invaluable insights into the mechanism of viral DNA recognition and packaging in general. Our results are likely to have a broad appeal to the scientific community and could answer long standing questions in Virology and Bacterial Evolution. Almost all aspects of modern medicine rely on effective antibiotics but this is being undermined by the alarming spread of antibiotic resistance. Understanding the methods used by microbes to rapidly acquire virulence genes is crucial if we are to develop new treatments or even to preserve the current antimicrobial armoury.

水平基因转移（HGT）是细菌之间基因交换的基本和强大过程。 HGT驱动细菌的进化，适应并扩散到新的生态壁ches中，是快速分布抗生素耐药性和致病性等特征的主要手段。感染细菌的病毒被称为噬菌体，或者仅仅是噬菌体，通常被认为是HGT最具影响力的机制。基因转移剂（GTA）是与噬菌体有关的小病毒颗粒，并且能够在细菌细胞之间滥交几乎所有基因。对GTA在环境中的活性的研究表明，抗生素耐药性基因可以在极高的频率下传播，因此在病原体中GTA介导的抗生素耐药性和毒力基因的传播具有巨大的潜在临床和经济后果。该研究项目的总体目标是使GTA DNA识别机器的结构和功能表征。病毒通常是自私的元素，其主要目标是利用宿主的资源来制作自己的副本，然后继续感染新宿主。尽管在许多方面与传统病毒相似，但GTA并没有复制自己的基因组，也不会以牺牲宿主为代价来促进自己的生存。相反，GTA将其细菌宿主的整个基因组包装成咬伤，并将其分配给受体细菌。当产生GTA的物种包含用于增强发病机理或抗生素耐药性的基因时，这种不加区分的基因转移将成为极大的关注。在噬菌体中，负责对噬菌体基因组的特定识别的蛋白质称为小末端酶。小末端酶还调节大端酶蛋白的酶促活性，该蛋白切割了靶DNA并将其迅速喂入预先形成的空病毒头直至整个基因组包装。尽管由于经典的ATP水解序列基序，通过生物信息学很容易鉴定出GTA大末端酶，但尚未鉴定出GTA小末端酶。我们的初步数据提供了第一个证据，证明GTA具有小末端酶，并允许在其他不同GTA中预测类似的小末端酶。我们将检查GTA小末端的生物化学和结构，这将允许定义这些非典型末端的基本特性，以提高新型GTA的检测效率，并为一般而言的病毒DNA识别和包装机制提供无价的见解。我们的结果可能对科学界有广泛的吸引力，并且可以回答病毒学和细菌进化中长期存在的问题。现代医学的几乎所有方面都依赖于有效的抗生素，但由于抗生素耐药性的惊人传播而受到破坏。如果要开发新的治疗方法，甚至保留当前的抗菌疗法，那么了解微生物迅速获得毒力基因的方法至关重要。