Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Genet. 2012;8(6):e1002733. doi: 10.1371/journal.pgen.1002733. Epub 2012 Jun 14.
The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. Here we show that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we show that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (∼1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data show that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens.
秀丽隐杆线虫为进行高通量、活体动物的小分子化合物文库筛选，以鉴定靶向各种细胞过程的分子提供了目前尚未开发的潜力。我们之前使用秀丽隐杆线虫中的细菌感染测定法，在 37214 种测试化合物中鉴定出 119 种影响宿主-微生物相互作用的化合物。在这里，我们发现这些小分子化合物中的一种，RPW-24，通过刺激线虫的宿主免疫反应来保护秀丽隐杆线虫免受细菌感染。通过转录组谱分析、秀丽隐杆线虫突变体的上位通路分析和 RNAi 筛选，我们表明 RPW-24 通过诱导线虫中数量非常少的基因（约占所有基因的 1.3%）的转录来促进对铜绿假单胞菌感染的抗性，这种方式部分依赖于进化保守的 p38 MAP 激酶途径和转录因子 ATF-7。这些数据表明，RPW-24 的免疫刺激活性是其功效所必需的，并定义了一种基于秀丽隐杆线虫的新策略，以鉴定对抗生素耐药的细菌病原体具有活性的化合物。
