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

基本信息

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

项目摘要

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且强大的过程。 HGT 驱动细菌进化、适应并扩散到新的生态位，是抗生素耐药性和致病性等特征快速分布的主要手段。感染细菌的病毒被称为噬菌体，或简称为噬菌体，通常被认为是 HGT 最有影响力的机制。基因转移剂 (GTA) 是与噬菌体相关的小病毒颗粒，能够在细菌细胞之间无差别地转移几乎任何基因。对环境中 GTA 活性的研究表明，抗生素抗性基因可以以极高的频率传播，因此 GTA 介导的抗生素抗性和毒力基因在病原体中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为了表征 GTA DNA 识别机制的结构和功能。病毒通常是自私的元素，其主要目标是利用宿主的资源来复制自身，然后继续感染新宿主。尽管 GTA 在很多方面与传统病毒相似，但 GTA 不会复制自己的基因组，也不会以牺牲宿主为代价来促进自身生存。相反，GTA 将其细菌宿主的整个基因组包装成一口大小的片段，并将其分发给受体细菌。当产生 GTA 的物种含有增强发病机制或抗生素耐药性的基因时，这种不加区别的基因转移就会引起极大的关注。在噬菌体中，负责特异性识别噬菌体基因组的蛋白质称为小终止酶。小终止酶还调节大终止酶蛋白的酶活性，大终止酶蛋白切割靶DNA并快速将其送入预先形成的空病毒头中，直到包装整个基因组。尽管由于经典的 ATP 水解序列基序，GTA 大终止酶很容易通过生物信息学鉴定，但尚未鉴定出 GTA 小终止酶。我们的初步数据提供了第一个证据，证明 GTA 具有小终止酶，并允许预测其他不同物种中类似的小终止酶GTAs。我们将研究 GTA 小末端酶的生物化学和结构，这将允许定义这些非典型末端酶的基本特性，以提高新型 GTA 的检测效率，并为病毒 DNA 识别和识别机制提供宝贵的见解。包装一般。我们的结果可能对科学界具有广泛的吸引力，并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，但抗生素耐药性的惊人蔓延正在破坏这一点。如果我们要开发新的治疗方法，甚至保护现有的抗菌库，了解微生物快速获取毒力基因的方法至关重要。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Jorvik: A membrane-containing phage that will likely found a new family within Vinavirales.

DOI：
10.1016/j.isci.2023.108104
发表时间：
2023-11-17
期刊：
ISCIENCE
影响因子：
5.8
作者：
Bardy, Pavol;MacDonald, Conor I. W.;Pantucek, Roman;Antson, Alfred A.;Fogg, Paul C. M.
通讯作者：
Fogg, Paul C. M.

Gene transfer agents: The ambiguous role of selfless viruses in genetic exchange and bacterial evolution