The source of genomic innovation in the human pathogen Acinetobacter baumannii

人类病原体鲍曼不动杆菌基因组创新的来源

• 批准号: 258357013
• 负责人: Professor Dr. Ingo Ebersberger
• 金额: --
• 依托单位: Institut für Zellbiologie und Neurowissenschaft
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258357013?language=en
• 关键词: source; genomic; innovation; human; pathogen

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.

在拟议的项目中，我们描绘了鲍曼不动杆菌从一种良性环境细菌转变为威胁生命的人类病原体的进化轨迹。 在一个概念性的方法，我们调查如何A。鲍曼尼完成了这一转变的相关关键创新。我们专注于水平基因转移的贡献，强调环境DNA的直接摄取，以及对不动杆菌属中预先存在的基因的修饰。进化枝我们的建议的补充，应用部分的目的是阐明宿主感染过程中的基因表达程序，提供一个替代的途径来了解A。鲍曼不动杆菌毒力总之，我们的研究结果将有助于发展一个进化的系统观A。鲍曼不动杆菌感染，这是今后控制该病原体的必要前提。我们将开始调查的一般作用，水平基因转移的遗传创新和生态位适应。由于重建的基因组序列中的污染会严重损害这些分析，我们将建立一个水平基因转移事件的最小信息标准。通过对A. baumannii水平获得的基因，我们将确定遗传信息流入和内A。鲍曼不动杆菌。与此同时，我们在不同的吸收情况下，水平获得的基因的基因组分布模型。将这些模型拟合到观察到的分布将有助于评估许多A的条件自然能力是否以及在多大程度上。鲍曼不动杆菌菌株使它们能够挖掘其周围的遗传多样性，以寻找传递适应性优势的基因。然后，我们将着手解开A的机械基础。鲍曼不动杆菌毒力在方法层面上，将蛋白质3-D结构比较实施到我们的特征感知系统分析软件中，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综合性。然后我们将筛选A。鲍曼不动杆菌泛基因组，其功能多样化的预测时间点可与毒力的种或株特异性变化相关联。这种基于比较基因组学的毒力因子的预测将与病原体和不同宿主系统在感染时程中的基因表达的深入分析相补充。这种双组学方法有三个主要目标：它将作为计算机预测的候选毒力因子的可扩展的第一级评估。它将有助于识别通过基因表达上调介导的毒力贡献或代表非编码RNA的候选物。最终揭示了A.感染过程中的鲍曼不动杆菌基因，以及其对不同人体组织和不同宿主物种的可塑性。