Determinants underlying horizontal gene transfer-mediated pathogen success

项目摘要 水平基因转移(Hgt)，特别是质粒连接，是微生物进化的驱动力。 和发病机制。接合的过程看起来似乎很简单：供体细胞转移一个拷贝 通过物理交配桥将质粒连接到相容的受体细胞。在这样做的过程中，不同的特征， 例如新陈代谢、毒力和抗生素耐药性基因，都可以传播。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，产生了各种各样的潜在菌株/质粒组合；尽管 这一点，流行病学监测清楚地表明，只有少数克隆人和他们的 相关的质粒在原地持续存在，并在不同的生态，地理， 和临床情况。因此，人们普遍认为，单个菌株-质粒对的总体适合度 是成功病原体的一个关键特征。从根本上说，这种成功是由动态交互推动的 在有利的环境中，携带质粒的供体和合适的受体菌株之间的关系，导致 形成新的菌株-质粒对(例如，转接子)。然而，到目前为止，研究主要是 专注于已建立的菌株-质粒组合(例如，供体能力和/或质粒适合性 成本)；相比之下，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 制定策略，在质粒在种群中确立之前对其进行干预。 为了解决这一差距，我的研究计划利用我们在以下领域的独特跨学科专业知识 用计算模型、生物信息学和机械实验来研究分子 有利于形成新的菌株-质粒组合的因素。我们提出的主题就是这样 从三个互补的角度看问题：(1)是什么遗传特征决定了某些质粒 更难/更容易获得？(2)是什么决定了一种菌株作为良好的HGT接受者的潜力？ 环境选择如何影响质粒获取能力？加在一起，这些平行的 目标致力于一个统一的框架，该框架集成了跨多个复杂级别的见解 (即从分子到生态/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，即可靠地预测(并最终控制)临床 相关的菌株/质粒流行，并最终使我们能够预见病原体的出现 先验和探索下游应用，例如，新的抗生素治疗策略。

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.