Novel Immune Modulators Enhance <i>Caenorhabditis elegans</i> Resistance to Multiple Pathogens.

Traditional treatments for bacterial infection have focused upon directly inhibiting growth of the pathogen. However, an equally important determinant of infection outcome is the host defense response. We previously performed a high-throughput chemical screen to identify small molecules that rescued the nematode Caenorhabditis elegans from infection by Pseudomonas aeruginosa. Over 20 of the hits stimulated host defense gene expression. During in-depth studies of five such molecules using microarray analysis, bioinformatic clustering, and RNAi knockdown of candidate gene targets, we identified PMK-1/p38 MAPK and SKN-1/Nrf2 as two key pathways modulated by these hits. Interestingly, the molecules studied did not depend on a single pathway for ameliorating P. aeruginosa pathogenesis in liquid-based assay, but did rely on the PMK-1/p38 MAPK pathway during a colonization-based infection assay on agar. A subset of these molecules was also protective against Enterococcus faecalis and Staphylococcus aureus. In general, the compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. These molecules possess significant potential for use as tools to study innate immune processes细菌性感染的传统治疗策略，长期以来聚焦于直接抑制病原菌的生长。然而，感染结局的另一同等关键决定因素，乃是宿主防御反应。此前我们开展了一项高通量化学筛选，旨在鉴定可使秀丽隐杆线虫（Caenorhabditis elegans）免受铜绿假单胞菌（Pseudomonas aeruginosa）感染的小分子化合物。最终筛选得到的命中化合物中，有超过20种可激活宿主防御基因的表达。在采用基因芯片分析、生物信息学聚类以及候选基因靶点RNA干扰敲低技术，对其中5种化合物进行深入研究后，我们鉴定出PMK-1/p38丝裂原活化蛋白激酶（MAPK）与SKN-1/Nrf2这两条被此类命中化合物调控的核心通路。值得注意的是，在所研究的化合物中，在液体培养检测体系内缓解铜绿假单胞菌致病作用的过程并不依赖单一通路；但在琼脂平板的定植型感染检测实验中，则必须依赖PMK-1/p38 MAPK通路。此类化合物中的一部分，同时对粪肠球菌（Enterococcus faecalis）与金黄色葡萄球菌（Staphylococcus aureus）具有感染防护作用。总体而言，这些化合物对哺乳动物细胞或线虫几乎无毒性，这与其通过表型型高内涵筛选获得的筛选逻辑相符。上述化合物具备作为研究天然免疫过程的工具的巨大应用潜力。