The source of genomic innovation in the human pathogen Acinetobacter baumannii

在拟议的项目中，我们描绘了鲍曼不动杆菌从良性环境细菌转变为威胁生命的人类病原体的进化轨迹。 在概念方法中，我们研究了鲍曼不动杆菌如何实现这一转变的相关关键创新。我们既关注水平基因转移的贡献，重点关注环境 DNA 的直接摄取，也关注不动杆菌属中预先存在的基因的修饰。进化枝。我们提案的补充应用部分旨在阐明宿主感染期间的基因表达程序，为理解鲍曼不动杆菌毒力提供另一种途径。总而言之，我们的结果将有助于形成鲍曼不动杆菌感染的进化系统观点，这是未来控制这种病原体的必要先决条件。我们将首先研究水平基因转移对于遗传创新和生态位适应的一般作用。由于重建基因组序列中的污染会严重影响这些分析，因此我们将为水平基因转移事件建立最低限度的信息标准。通过筛选鲍曼不动杆菌的泛基因组中水平获得的基因，我们将确定鲍曼不动杆菌内部和内部的遗传信息通量。同时，我们对不同摄取场景下水平获得的基因的基因组分布进行建模。将这些模型与观察到的分布进行拟合将有助于评估许多鲍曼不动杆菌菌株的条件自然能力是否以及在多大程度上允许它们挖掘其周围的遗传多样性，以寻找具有适应性优势的基因。然后我们将继续揭示鲍曼不动杆菌毒力的机制基础。在方法层面上，将蛋白质 3-D 结构比较应用到我们的特征感知系统分析软件中，将为评估相关蛋白质之间的功能多样化程度增加另一层全面性。然后，我们将筛选鲍曼不动杆菌泛基因组中的蛋白质，这些蛋白质的功能多样化的预测时间点可以与物种或菌株特异性的毒力变化相关联。这种基于比较基因组学的毒力因子预测将与对病原体和不同宿主系统感染过程中基因表达的深入分析相补充。这种双组学方法具有三个主要目标： 它将作为计算机预测毒力因子候选物的可扩展的一级评估。它将有助于识别那些通过基因表达上调介导对毒力的贡献或代表非编码 RNA 的候选者。最终，它将揭示鲍曼不动杆菌基因在感染过程中的相互作用网络，及其对不同人体组织和不同宿主物种的可塑性。

In the proposed project, we delineate the evolutionary trajectory that has converted Acinetobacter baumannii from a benign environmental bacterium to a life-threatening human pathogen. In a conceptual approach, we investigate how A. baumannii has accomplished the relevant key innovations accounting for this transformation. We focus both on the contribution of horizontal gene transfer, with an emphasis on the direct uptake of environmental DNA, and the modification of genes that pre-existed in the Acinetobacter spp. clade. The complementary, applied part of our proposal aims at elucidating the gene expression program during host infection, providing an alternative path towards understanding A. baumannii virulence. Taken together, our results will contribute to developing an evolutionary systemic view on A. baumannii infection, a necessary prerequisite for controlling this pathogen in the future. We will begin with investigating the general role of horizontal gene transfer for genetic innovation and niche adaptation. Because contaminations in reconstructed genome sequences can severely compromise these analyses, we will establish a minimal information standard for a horizontal gene transfer event. By screening the pan-genome of A. baumannii for horizontally acquired genes, we will then determine the flux of genetic information into and within A. baumannii. In parallel, we model the genomic distribution of horizontally acquired genes under different uptake scenarios. Fitting these models to the observed distributions will help assessing if, and to what extent, the conditional natural competence of many A. baumannii strains allows them to mine their surrounding genetic diversity for genes conveying an adaptive advantage. We will then proceed towards unravelling the mechanistic basis of A. baumannii virulence. On the methods-level, the implementation of protein 3-D structure comparisons into our feature-aware phyletic profiling software, will add another layer of comprehensiveness in assessing the extent of functional diversification between related proteins. We will then screen the A. baumannii pan genome for proteins whose predicted time point of functional diversification can be linked to species- or strain-specific changes in virulence. This comparative genomics-based prediction of virulence factors will be complemented with an in-depth analysis of gene expression in a time course of infection, for both pathogen and a diverse set of hosts systems. This dual-omics approach has three main objectives: It will serve as a scalable first-level evaluation of the in-silico predicted virulence factor candidates. It will help identifying candidates whose contribution to virulence is mediated via an up-regulation of gene expression, or that represent non-coding RNAs. And ultimately, it will reveal the interaction network of A. baumannii genes during infection, together with its plasticity in response to different human tissues, and different host species.