Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
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.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Read
R
Pukkila-Worley
Rhonda
R
Feinbaum
Natalia V
NV
Kirienko
Jonah
J
Larkins-Ford
Annie L
AL
Conery
Frederick M
FM
Ausubel
D051696:Activating Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000276:immunology / Q000382:microbiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics*; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C575121:2-N-(3-chloro-4-methylphenyl)quinazoline-2,4-diamine; C551311:ATF-7 protein, C elegans; D051696:Activating Transcription Factors; D000900:Anti-Bacterial Agents; D029742:Caenorhabditis elegans Proteins; D011799:Quinazolines; D054852:Small Molecule Libraries; C013474:2,4-diaminoquinazoline; D048051:p38 Mitogen-Activated Protein Kinases