Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Camperdown, New South Wales, Australia.
The University of Sydney, Faculty of Science, Sydney School of Veterinary Science, Sydney, New South Wales, Australia.
PLoS Pathog. 2021 Apr 7;17(4):e1009186. doi: 10.1371/journal.ppat.1009186. eCollection 2021 Apr.
Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas.
致病分枝杆菌在感染过程中积极地扰乱保护性宿主免疫信号通路，以驱动允许性肉芽肿微环境的形成。宿主 microRNA（miRNA）表达的动态调控是分枝杆菌感染在宿主-病原体配对中的一个保守特征。在这里，我们研究了 miR-206 在斑马鱼感染嗜水气单胞菌模型中的作用，该模型允许研究肉芽肿形成的早期阶段。我们发现，感染致病性嗜水气单胞菌后 miR-206 上调，而 miR-206 反义寡核苷酸介导的敲低可抵抗感染。我们观察到感染 miR-206 敲低斑马鱼胚胎中 cxcl12a 和 cxcr4b 的显著上调，并且活体成像显示中性粒细胞向感染部位的募集增强。我们使用 CRISPR/Cas9 介导的 cxcl12a 和 cxcr4b 表达敲低以及 AMD3100 抑制 Cxcr4，表明 miR-206 敲低引起的增强中性粒细胞反应和减少细菌负荷依赖于 Cxcl12/Cxcr4 信号轴。总之，我们的数据说明了一条途径，即致病性分枝杆菌诱导宿主 miR-206 表达，以抑制 Cxcl12/Cxcr4 信号，并防止保护性中性粒细胞募集到肉芽肿中。
