The evolutionary repurposing of eukaryotic genes into bacterial effectors.

为了在宿主细胞内生存，细胞内的病原体进化了大量的效应蛋白，这些蛋白操纵宿主的过程，创造一个复制的生态位。嗜肺军团菌是最广泛的军团菌之一，它是一种细胞内细菌，通过在广泛的淡水原生动物中生长而持续存在于自然界。我的研究计划的目的是了解嗜肺性乳杆菌是如何侵占真核基因并将其重新用于细菌效应器的。 军团菌拥有300多个易位效应器和几个易于培养的宿主，是探索效应器进化基本机制的无与伦比的实验模型系统。许多军团菌效应器含有真核样结构域，提示它们可能是域间水平基因转移的产物。关于从原生动物基因到针对宿主过程的真正军团菌效应器的进化路径，人们知之甚少。在我的实验室在细菌基因组学和实验进化方面展示的专业知识的基础上，我们将绘制军团菌庞大的效应器武器库来自哪里，如何获得新的效应器，以及哪些进化过程支持水平获得的基因向真正的易位效应器的功能转变。 虽然其他研究集中在分离的军团菌效应器的生化活性上，但几种技术的融合使得以前难以解决但长期悬而未决的效应器起源和进化问题变得触手可及。利用比较基因组学、转录图谱和实验进化，我们将揭示继续塑造这些环境中无处不在的细菌的生态位和宿主范围的基本过程。我们预计，这些研究将为通过水平基因转移获得的基因的进化再利用提供广泛的基础性见解，这是细菌进化的关键贡献因素。

In order to survive inside host cells, intracellular pathogens have evolved arsenals of effector proteins that manipulate host processes to create a replicative niche. One of the most extensive arsenals is maintained by Legionella pneumophila, an intracellular bacterium that persists in nature by growing within a wide range of freshwater protozoa. The objective of my research program is to understand how L. pneumophila commandeers and repurposes eukaryotic genes into bacterial effectors. With a remarkably large cohort of over 300 translocated effectors and several easily cultivatable hosts, Legionella represents an unparalleled experimental model system to probe fundamental mechanisms of effector evolution. Many Legionella effectors contain eukaryotic-like domains, suggesting they may be the product of interdomain horizontal gene transfer. Little is known about the evolutionary path that leads from protozoan gene to a bona fide Legionella effector targeting host processes. Building on my lab's demonstrated expertise in bacterial genomics and experimental evolution, we will map where Legionella's large arsenal of effectors came from, how new effectors can be acquired, and what evolutionary processes support the functional transition of horizontally acquired genes into bona fide translocated effectors. While other studies have focused on the biochemical activity of isolated Legionella effectors, the confluence of several technologies has placed previously intractable but long outstanding questions about effector origin and evolution within our reach. Using comparative genomics, transcriptional profiling, and experimental evolution, we will uncover the fundamental processes that continue to shape the ecological niche and host range of these environmentally ubiquitous bacteria. We anticipate that these studies will provide broad foundational insight into the evolutionary repurposing of genes acquired through horizontal gene transfer, a critical contributor to bacterial evolution.