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），特别是质粒接合，是微生物进化的驱动力 和发病机制。接合的过程看似简单：供体细胞转移一个拷贝 通过物理交配桥将质粒转移到相容的受体细胞。在这样做的过程中，不同的特征， 例如代谢、毒力和抗生素抗性基因，可以被传播。因此，HGT一直是 涉及多种人类健康和工业应用，从多药耐药性到 生物修复微生物组研究的进展表明，HGT发生在两者之间， 和远亲菌株，产生广泛多样的潜在菌株/质粒组合;尽管 流行病学监测清楚地表明，只有一小部分克隆体及其 相关质粒在原位持续存在，并且在不同的生态，地理， 和临床背景。因此，人们普遍认为，单个菌株-质粒对的整体适合度 是成功病原体的关键特征从根本上说，这种成功是由一种动态的相互作用驱动的。 携带质粒的供体和合适的受体菌株在有利的环境中， 新菌株-质粒对的形成（例如，transconjugants）。然而，迄今为止的研究主要是 集中于已建立的菌株-质粒组合（例如，供体能力和/或质粒适合度 成本）;相反，有利于这些组合初步形成的动力和因素 是完全未知的。然而，这些信息对于预测新病原体的出现和 在质粒在人群中建立之前，制定干预质粒获得的策略。 为了解决这一差距，我的研究计划利用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来研究分子 有利于形成新菌株-质粒组合的因素。我们建议的主题接近这一点 从三个互补的角度提出问题：（1）哪些遗传特征使某些质粒 更难/更容易获得？(2)是什么决定了菌株作为良好HGT受体的潜力？（三） 环境选择如何影响质粒获取能力？结合起来，这些平行 这些目标致力于建立一个统一的框架，该框架整合了跨多个复杂级别的见解 (i.e.,分子到生态/进化）。这些研究方向有助于我们的长期目标， 一个是NIGMS使命的核心，即可靠地预测（并最终控制）临床 相关菌株/质粒的流行，并最终使我们能够预测病原体的出现， 先验和探索下游应用，例如，新的抗生素治疗策略。