The source of genomic innovation in the human pathogen Acinetobacter baumannii

在拟议的项目中，我们描绘了将鲍曼不动杆菌从一种良性环境细菌转变为一种威胁生命的人类病原体的进化轨迹。在概念性的方法中，我们调查了鲍曼氏杆菌是如何完成这一转变的相关关键创新的。我们既关注水平基因转移的贡献，强调环境DNA的直接吸收，也关注对不动杆菌中原有基因的修饰。克莱德。我们的建议的补充和应用部分旨在阐明宿主感染过程中的基因表达程序，为了解鲍曼不动杆菌的毒力提供另一种途径。综上所述，我们的结果将有助于发展对鲍曼不动杆菌感染的进化系统观，这是未来控制这种病原体的必要前提。我们将从研究水平基因转移对基因创新和生态位适应的一般作用开始。因为重组基因组序列中的污染会严重危及这些分析，我们将为水平基因转移事件建立一个最低限度的信息标准。通过筛选鲍曼不动杆菌的全基因组水平获得的基因，我们将确定遗传信息进入和进入鲍曼不动杆菌内的流量。同时，我们模拟了水平获取的基因在不同吸收场景下的基因组分布。将这些模型与观察到的分布相匹配，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他们挖掘周围的遗传多样性，以寻找传达适应优势的基因。然后，我们将着手解开鲍曼不动杆菌毒力的机制基础。在方法层面上，将蛋白质三维结构比较应用到我们的特征感知系统谱分析软件中，将在评估相关蛋白质之间功能多样化的程度方面增加另一层全面性。然后，我们将筛选鲍曼不动杆菌PAN基因组中的蛋白质，这些蛋白质的功能多样化预测时间点可以与物种或菌株特定毒力的变化联系在一起。这种基于比较基因组学的毒力因子预测将辅之以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。这种双重组学方法有三个主要目标：它将作为电子预测毒力因子候选的可扩展的第一级评估。这将有助于识别其毒力贡献是通过上调基因表达或代表非编码RNA的候选基因。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，以及它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.