Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
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DOI：
10.1371/journal.pgen.1002733
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Ausubel FM
中科院分区：
文献类型：
--
作者：
Pukkila-Worley R;Feinbaum R;Kirienko NV;Larkins-Ford J;Conery AL;Ausubel FM
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. Infections with antibiotic-resistant bacterial pathogens are increasing at an alarming rate, and there are very few new therapies currently being developed. We have identified a small molecule that protects the nematode C. elegans from bacterial infection by stimulating the host immune response, not by directly interfering with bacterial growth, which is the mechanism employed by all currently available antibiotics. In this study, we investigate the mode of action of this small molecule and demonstrate that it stimulates the expression of immune effector molecules via evolutionarily conserved immune regulators. These studies illustrate the potential of targeting host immunity for the treatment of bacterial infections and the advantages that C. elegans offers both to identify small molecules that target key cellular processes and to study their mechanism of action.
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影响因子：
30.3
作者：
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通讯作者：
Ausubel FM
影响因子：
64.5
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通讯作者：
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4
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通讯作者：
Ausubel, Frederick M.