Determinants underlying horizontal gene transfer-mediated pathogen success

水平基因转移介导的病原体成功的决定因素

• 批准号: 10713094
• 负责人: Allison Lopatkin
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713094
• 关键词: Address; Antibiotic Resistance; Antibiotic Therapy; Bioinformatics; Bioremediations; Cells; Clinical; Communicable Diseases; Computer Models; Distant; Environment; Environmental Risk Factor; Epidemiologic Monitoring; Event; Evolution; Gene Transfer; Genetic; Genetic Materials; Geography; Goals; Health; Horizontal Gene Transfer; Human; In Situ; Individual; Industrialization; Mediating; Metabolic; Methods; Minority; Mission; Molecular; Multi-Drug Resistance; National Institute of General Medical Sciences; Partner in relationship; Pathogenesis; Plasmids; Population; Prevalence; Process; Research; Time; Virulence; Work; clinically relevant; cost; driving force; emerging pathogen; experimental study; fitness; high risk; insight; microbial; microbiome research; novel; pathogen; programs; resistance gene; success; trait; treatment strategy

Project Summary Horizontal gene transfer (HGT), specifically plasmid conjugation, is a driving force in microbial evolution and pathogenesis. The process of conjugation appears deceptively simple: a donor cell transfers a copy of a plasmid to a compatible recipient cell through a physical mating bridge. In doing so, diverse traits, such as metabolic, virulence, and antibiotic resistance genes, can be spread. As such, HGT has been implicated in a variety of human health and industrial applications, ranging from multi-drug resistance to bioremediation. Advances in microbiome studies have revealed that HGT occurs between both closely and distantly related strains, yielding a wide diversity of potential strain/plasmid combinations; despite this, epidemiological surveillance clearly demonstrates that only a small minority of clones and their associated plasmids persist in situ and are highly conserved across different ecological, geographical, and clinical contexts. Thus, it is widely believed that the overall fitness of individual strain-plasmid pairs is a key feature of successful pathogens. Fundamentally, this success is driven by a dynamic interaction between a plasmid-carrying donor and suitable recipient strain in a favorable environment, resulting in the formation of new strain-plasmid pairs (e.g., transconjugants). However, research to date has primarily focused on established strain-plasmid combinations (e.g., donor capabilities and/or plasmid fitness costs); in contrast, the dynamics and factors favoring the initial formation of these combinations are entirely unknown. Yet, such information is critical to both predict new pathogen emergence and develop strategies that intervene in plasmid acquisition before they become established in a population. To address this gap, my research program leverages our unique interdisciplinary expertise in computational modeling, bioinformatics, and mechanistic experiments to investigate the molecular factors favoring the formation of new strain-plasmid combinations. Our proposed themes approach this problem from three complementary perspectives: (1) What genetic features make certain plasmids harder/easier to acquire? (2) What determines a strain’s potential to act as a good HGT recipient? (3) How does environmental selection impact plasmid acquisition capabilities? Combined, these parallel objectives work towards a unified framework that integrates insights across multiple levels of complexity (i.e., molecular to ecological/evolutionary). These research directions contribute to our long-term goal, one that is central to the NIGMS mission, of reliably predicting (and ultimately controlling) clinically relevant strain/plasmid prevalence, and will eventually enable us to anticipate pathogen emergence a priori and explore downstream applications, e.g., novel antibiotic treatment strategies.

项目摘要 水平基因转移（HGT），特别是质粒结合，是微生物进化的驱动力 和发病机理。结合过程似乎很简单：供体单元转移副本 通过物理交配桥到兼容受体细胞的质粒。这样，潜水员的特征， 例如代谢，病毒和抗生素耐药性基因可以传播。因此，HGT一直是 在各种人类健康和工业应用中实施，从多药抵抗到 生物修复。微生物组研究的进步表明，HGT发生在两者之间 以及远距离相关的菌株，产生了广泛的潜在应变/质粒组合的多样性；目的地 这个流行病学监测清楚地表明，只有少数克隆及其 相关的质粒原地持续存在，并且在不同的生态，地理，地理， 和临床环境。这是广泛认为，单个应变质量对的整体适应性 是成功病原体的关键特征。从根本上讲，这种成功是由动态互动驱动的 在有利的环境中，在质粒的供体和合适的受体应变之间，导致 新的应变质粒对的形成（例如，跨结合体）。但是，迄今为止的研究有主要 专注于已建立的应变质粒组合（例如，供体能力和/或质粒适应性 费用）；相反，有利于初始形成这些组合的动态和因素 完全未知。然而，这些信息对于预测新的病原体出现和 制定策略，以在质粒中介入之前介入质粒。 为了解决这一差距，我的研究计划利用了我们独特的跨学科专业知识 计算建模，生物信息学和机械实验，以研究分子 有利于形成新应变质量组合的因素。我们提出的主题将 从三个完整的角度来看：（1）哪些遗传特征使某些质粒 更难/更容易获取？ （2）是什么决定了菌株成为良好HGT接收者的潜力？ （3） 环境选择如何影响质粒获取能力？合并，这些平行 目标朝着一个统一的框架，该框架整合了跨多个复杂性的洞察力 （即，分子到生态/进化）。这些研究方向有助于我们的长期目标， 这是NIGMS任务的核心，可靠地预测（并最终控制）临床 相关菌株/质粒患病率，最终将使我们能够预期病原体出现 先验和探索下游应用，例如新型的抗生素治疗策略。