RRC ID 46425
Author Pukkila-Worley R, Feinbaum R, Kirienko NV, Larkins-Ford J, Conery AL, Ausubel FM.
Title Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
Journal PLoS Genet.
Abstract 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.
Volume 8(6)
Pages e1002733
Published 2012
DOI 10.1371/journal.pgen.1002733
PII PGENETICS-D-12-00021
PMID 22719261
PMC PMC3375230
MeSH Activating Transcription Factors* / genetics Activating Transcription Factors* / immunology Activating Transcription Factors* / metabolism Animals Anti-Bacterial Agents / chemical synthesis Anti-Bacterial Agents / pharmacology Caenorhabditis elegans* / immunology Caenorhabditis elegans* / microbiology Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / immunology Caenorhabditis elegans Proteins* / metabolism Gene Expression Regulation / immunology Host-Pathogen Interactions / genetics* Immunity, Innate* MAP Kinase Signaling System / genetics MAP Kinase Signaling System / immunology Oligonucleotide Array Sequence Analysis Pseudomonas Infections / genetics Pseudomonas Infections / immunology Pseudomonas aeruginosa / pathogenicity Quinazolines* / chemical synthesis Quinazolines* / chemistry Quinazolines* / pharmacology RNA Interference Small Molecule Libraries / chemical synthesis Small Molecule Libraries / pharmacology p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / immunology p38 Mitogen-Activated Protein Kinases / metabolism
IF 5.54
Times Cited 29
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm4067