Applied Bioinformatics Group, Inst. of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt am Main, Germany.
Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, United States of America.
PLoS Genet. 2022 Jun 2;18(6):e1010020. doi: 10.1371/journal.pgen.1010020. eCollection 2022 Jun.
Nosocomial pathogens of the Acinetobacter calcoaceticus-baumannii (ACB) complex are a cautionary example for the world-wide spread of multi- and pan-drug resistant bacteria. Aiding the urgent demand for novel therapeutic targets, comparative genomics studies between pathogens and their apathogenic relatives shed light on the genetic basis of human-pathogen interaction. Yet, existing studies are limited in taxonomic scope, sensing of the phylogenetic signal, and resolution by largely analyzing genes independent of their organization in functional gene clusters. Here, we explored more than 3,000 Acinetobacter genomes in a phylogenomic framework integrating orthology-based phylogenetic profiling and microsynteny conservation analyses. We delineate gene clusters in the type strain A. baumannii ATCC 19606 whose evolutionary conservation indicates a functional integration of the subsumed genes. These evolutionarily stable gene clusters (ESGCs) reveal metabolic pathways, transcriptional regulators residing next to their targets but also tie together sub-clusters with distinct functions to form higher-order functional modules. We shortlisted 150 ESGCs that either co-emerged with the pathogenic ACB clade or are preferentially found therein. They provide a high-resolution picture of genetic and functional changes that coincide with the manifestation of the pathogenic phenotype in the ACB clade. Key innovations are the remodeling of the regulatory-effector cascade connecting LuxR/LuxI quorum sensing via an intermediate messenger to biofilm formation, the extension of micronutrient scavenging systems, and the increase of metabolic flexibility by exploiting carbon sources that are provided by the human host. We could show experimentally that only members of the ACB clade use kynurenine as a sole carbon and energy source, a substance produced by humans to fine-tune the antimicrobial innate immune response. In summary, this study provides a rich and unbiased set of novel testable hypotheses on how pathogenic Acinetobacter interact with and ultimately infect their human host. It is a comprehensive resource for future research into novel therapeutic strategies.
鲍曼不动杆菌复合群（ACB）的医院病原体是一个警示性的例子，说明了多药和泛耐药细菌在全球范围内的传播。为了满足对新型治疗靶点的迫切需求，对病原体与其非致病亲属之间的比较基因组学研究揭示了人类病原体相互作用的遗传基础。然而，现有研究在分类范围、系统发育信号的感知以及通过主要分析与功能基因簇无关的基因来解决分辨率方面存在局限性。在这里，我们在一个整合了基于同源性的系统发育分析和微同线性保守分析的系统发育基因组学框架中探索了超过 3000 个不动杆菌基因组。我们描绘了模式菌株鲍曼不动杆菌 ATCC 19606 中的基因簇，这些基因簇的进化保守性表明所包含基因的功能整合。这些进化稳定的基因簇（ESGCs）揭示了代谢途径、转录调节剂位于其靶标旁边，但也将具有不同功能的亚簇联系在一起，形成更高阶的功能模块。我们将 150 个 ESGC 列入候选名单，这些基因簇要么与致病性 ACB 进化枝同时出现，要么优先存在于其中。它们提供了一个高分辨率的遗传和功能变化的图片，与 ACB 进化枝中致病性表型的表现相一致。关键创新是通过中间信使连接 LuxR/LuxI 群体感应的调控效应器级联的重塑，以用于生物膜形成，扩展微营养素摄取系统，以及通过利用人类宿主提供的碳源来增加代谢灵活性。我们可以通过实验证明，只有 ACB 进化枝的成员才将色氨酸作为唯一的碳和能源来源，色氨酸是人类用来微调抗菌先天免疫反应的物质。总之，这项研究提供了一组丰富而无偏见的新的可测试假设，说明了致病性不动杆菌如何与最终感染其人类宿主相互作用。这是未来研究新型治疗策略的综合资源。
