The evolutionary repurposing of eukaryotic genes into bacterial effectors.

为了在宿主细胞内生存，细胞内病原体已经进化出操纵宿主过程以创建复制生态位的效应蛋白的武库。最广泛的武器库之一是由嗜肺军团菌维持的，嗜肺军团菌是一种细胞内细菌，通过在各种淡水原生动物中生长而在自然界中持续存在。我的研究计划的目标是了解L。pneumophila征用并将真核基因重新利用为细菌效应子。 军团菌拥有超过300个易位效应子和几个易于培养的宿主，是一个无与伦比的实验模型系统，可用于探索效应子进化的基本机制。许多军团菌效应子含有真核生物样结构域，表明它们可能是结构域间水平基因转移的产物。我们对从原生动物基因到真正的军团菌效应子靶向宿主过程的进化路径知之甚少。基于我的实验室在细菌基因组学和实验进化方面的专业知识，我们将绘制军团菌大量效应物的来源，如何获得新的效应物，以及什么样的进化过程支持水平获得的基因功能转变为真正的易位效应物。 虽然其他研究集中在孤立的军团菌效应的生化活性，几种技术的融合已经把以前棘手的，但长期悬而未决的问题效应器的起源和进化在我们的范围内。使用比较基因组学，转录谱和实验进化，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.