Section of Paediatric Infectious Diseases and Allergy, Department of Medicine, Imperial College London, London, UK.
Division of Paediatric Infectious Diseases, Dr von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Sci Rep. 2018 Jan 12;8(1):661. doi: 10.1038/s41598-017-18528-y.
Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood. Here we show that during infection of human whole blood with M. tuberculosis, host gene transcriptional suppression, rather than activation, is the predominant response. Spatial, temporal and functional characterisation of repressed genes revealed their involvement in pathogen sensing and phagocytosis, degradation within the phagolysosome and antigen processing and presentation. To identify mechanisms underlying suppression of multiple immune genes we undertook epigenetic analyses. We identified significantly differentially expressed microRNAs with known targets in suppressed genes. In addition, after searching regions upstream of the start of transcription of suppressed genes for common sequence motifs, we discovered novel enriched composite sequence patterns, which corresponded to Alu repeat elements, transposable elements known to have wide ranging influences on gene expression. Our findings suggest that to survive within infected cells, mycobacteria exploit a complex immune "molecular off switch" controlled by both microRNAs and Alu regulatory elements.
结核分枝杆菌（M. tuberculosis）通过颠覆免疫机制在人体巨噬细胞内生存和繁殖。尽管这些免疫逃避策略在功能上得到了很好的描述，但潜在的分子机制仍知之甚少。在这里，我们表明，在人类全血感染结核分枝杆菌时，宿主基因转录抑制而不是激活是主要反应。受抑制基因的空间、时间和功能特征表明它们参与病原体感应和吞噬作用、吞噬体中的降解以及抗原加工和呈递。为了确定多个免疫基因抑制的机制，我们进行了表观遗传学分析。我们鉴定了具有已知靶标的差异表达 microRNA。此外，在搜索受抑制基因转录起始上游区域的常见序列基序后，我们发现了新的富集复合序列模式，这些模式对应于 Alu 重复元件，这是一种已知对基因表达有广泛影响的转座元件。我们的研究结果表明，为了在受感染的细胞内生存，分枝杆菌利用复杂的免疫“分子关闭开关”，由 microRNA 和 Alu 调节元件共同控制。
