Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, Retzius väg 8,Stockholm, Sweden.
BMC Genomics. 2011 Feb 21;12:123. doi: 10.1186/1471-2164-12-123.
Mucosal infections elicit inflammatory responses via regulated signaling pathways. Infection outcome depends strongly on early events occurring immediately when bacteria start interacting with cells in the mucosal membrane. Hitherto reported transcription profiles on host-pathogen interactions are strongly biased towards in vitro studies. To detail the local in vivo genetic response to infection, we here profiled host gene expression in a recent experimental model that assures high spatial and temporal control of uropathogenic Escherichia coli (UPEC) infection within the kidney of a live rat.
Transcriptional profiling of tissue biopsies from UPEC-infected kidney tissue revealed 59 differentially expressed genes 8 h post-infection. Their relevance for the infection process was supported by a Gene Ontology (GO) analysis. Early differential expression at 3 h and 5 h post-infection was of low statistical significance, which correlated to the low degree of infection. Comparative transcriptomics analysis of the 8 h data set and online available studies of early local infection and inflammation defined a core of 80 genes constituting a "General tissue response to early local bacterial infections". Among these, 25% were annotated as interferon-γ (IFN-γ) regulated. Subsequent experimental analyses confirmed a systemic increase of IFN-γ in rats with an ongoing local kidney infection, correlating to splenic, rather than renal Ifng induction and suggested this inter-organ communication to be mediated by interleukin (IL)-23. The use of comparative transcriptomics allowed expansion of the statistical data handling, whereby relevant data could also be extracted from the 5 h data set. Out of the 31 differentially expressed core genes, some represented specific 5 h responses, illustrating the value of comparative transcriptomics when studying the dynamic nature of gene regulation in response to infections.
Our hypothesis-free approach identified components of infection-associated multi-cellular tissue responses and demonstrated how a comparative analysis allows retrieval of relevant information from lower-quality data sets. The data further define marked representation of IFN-γ responsive genes and a prompt inter-organ communication as a hallmark of an early local tissue response to infection.
黏膜感染通过调控信号通路引发炎症反应。感染结局很大程度上取决于细菌与黏膜细胞相互作用时即刻发生的早期事件。迄今为止，有关宿主-病原体相互作用的转录谱分析严重偏向于体外研究。为详细描述宿主对感染的局部体内遗传反应，我们在最近的一项实验模型中对组织进行基因表达谱分析，该模型可在活体大鼠肾脏中对尿路致病性大肠杆菌（UPEC）感染进行高度时空控制。
对 UPEC 感染肾脏组织的组织活检进行转录谱分析，发现感染后 8 小时有 59 个差异表达基因。GO 分析支持这些基因与感染过程的相关性。感染后 3 小时和 5 小时的早期差异表达具有较低的统计学意义，这与感染程度较低有关。对 8 小时数据集和在线可获得的早期局部感染和炎症的比较转录组学分析定义了一个由 80 个基因组成的“早期局部细菌感染的一般组织反应”核心。其中，25%被注释为干扰素-γ（IFN-γ）调控。随后的实验分析证实，局部肾脏感染大鼠体内 IFN-γ 呈全身性增加，与脾而非肾 Ifng 诱导相关，并表明这种器官间通讯是由白细胞介素（IL）-23 介导的。比较转录组学的使用扩展了统计数据处理，从而也可以从 5 小时数据集提取相关数据。在 31 个差异表达的核心基因中，有些代表特定的 5 小时反应，这说明了比较转录组学在研究感染相关基因调控的动态性质时的价值。
我们的无假设方法确定了感染相关多细胞组织反应的组成部分，并展示了比较分析如何从低质量数据集检索相关信息。这些数据进一步定义了 IFN-γ 反应基因的显著表达和早期局部组织对感染的快速器官间通讯是其特征。
