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.

项目概要 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。 通过物理交配桥的质粒到兼容的受体细胞。 诸如代谢，毒力和抗生素耐药性基因可以传播。 与各种人类健康和工业应用有关，从多药抵抗到 生物修复。 远距离菌株，尽管有多种潜在的应变/质粒组合 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，地理位置上是高度保守的 和临床环境。 是成功的病原体的关键特征。 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 新的应变质量对的形成（例如，跨结合者）。 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 成本）；相比之下，有利于初始组合的动态 完全未知。 制定策略在建立质粒之前干预质粒的策略成为人群。 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 有利于形成新的应变质量组合的因素。 从三个互补角度来看：（1）哪些遗传特征使某些质粒 更难/更容易获取？ 环境选择如何影响质粒的获取能力？ 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。