Stimulation of Host Immune Defenses by a Small Molecule Protects 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.
Vyšlo v časopise:
Stimulation of Host Immune Defenses by a Small Molecule Protects from Bacterial Infection. PLoS Genet 8(6): e32767. doi:10.1371/journal.pgen.1002733
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002733
Souhrn
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.
Zdroje
1. MoyTIConeryALLarkins-FordJWuGMazitschekR 2009 High-throughput screen for novel antimicrobials using a whole animal infection model. ACS Chem Biol 4 527 533
2. MoyTIBallARAnklesariaZCasadeiGLewisK 2006 Identification of novel antimicrobials using a live-animal infection model. Proc Natl Acad Sci USA 103 10414 10419
3. Pukkila-WorleyRHolsonEWagnerFMylonakisE 2009 Antifungal Drug Discovery through the Study of Invertebrate Model Hosts. Curr Med Chem 16 1588 1595
4. Pukkila-WorleyRAusubelFM 2012 Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24 3 9
5. Pukkila-WorleyRAusubelFMMylonakisE 2011 Candida albicans Infection of Caenorhabditis elegans Induces Antifungal Immune Defenses. PLoS Pathog 7 e1002074 doi:10.1371/journal.ppat.1002074
6. Pukkila-WorleyRPelegAYTampakakisEMylonakisE 2009 Candida albicans hyphal formation and virulence assessed using a Caenorhabditis elegans infection model. Eukaryotic Cell 8 1750 1758
7. Pukkila-WorleyRMylonakisE 2010 From the outside in and the inside out: Antifungal immune responses in Caenorhabditis elegans. Virulence 1 111 112
8. TroemelERChuSWReinkeVLeeSSAusubelFM 2006 p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans PLoS Genet 2 e183 doi:10.1371/journal.pgen.0020183
9. IrazoquiJETroemelERFeinbaumRLLuhachackLGCezairliyanBO 2010 Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus PLoS Pathog e1000982 6 doi:10.1371/journal.ppat.1000982
10. KimDHFeinbaumRAlloingGEmersonFEGarsinDA 2002 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297 623 626
11. ShiversRPKooistraTChuSWPaganoDJKimDH 2009 Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. Cell Host Microbe 6 321 330
12. ShiversRPPaganoDJKooistraTRichardsonCEReddyKC 2010 Phosphorylation of the Conserved Transcription Factor ATF-7 by PMK-1 p38 MAPK Regulates Innate Immunity in Caenorhabditis elegans PLoS Genet e1000892 6 doi:10.1371/journal.pgen.1000892
13. BolzDDTenorJLAballayA 2010 A conserved PMK-1/p38 MAPK is required in Caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection. J Biol Chem 285 10832 10840
14. O'RourkeDBabanDDemidovaMMottRHodgkinJ 2006 Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res 16 1005 1016
15. TanMWMahajan-MiklosSAusubelFM 1999 Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci USA 96 715 720
16. PowellJRKimDHAusubelFM 2009 The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response. Proc Natl Acad Sci USA 106 2782 2787
17. EstesKADunbarTLPowellJRAusubelFMTroemelER 2010 bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans. Proc Natl Acad Sci USA 107 2153 2158
18. Reece-HoyesJSDeplanckeBShinglesJGroveCAHopeIA 2005 A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks. Genome Biol 6 R110
19. AmsdenGWBallowCHBertinoJSJKashubaAD 2005 Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. MandellGLBennettJEDolinR 271 281 Principals and Practice of Infectious Diseases. Philadelphia, PA: Elsevier.
20. McElweeJJSchusterEBlancEThomasJHGemsD 2004 Shared transcriptional signature in Caenorhabditis elegans dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem 279 44533 44543
21. ReichertKMenzelR 2005 Expression profiling of five different xenobiotics using a Caenorhabditis elegans whole genome microarray. Chemosphere 61 229 237
22. MeloJARuvkunG 2012 Inactivation of Conserved C. elegans Genes Engages Pathogen- and Xenobiotic-Associated Defenses. Cell 149 452 466
23. AnJHBlackwellTK 2003 SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17 1882 1893
24. InoueHHisamotoNAnJHOliveiraRPNishidaE 2005 The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev 19 2278 2283
25. AnJHVranasKLuckeMInoueHHisamotoN 2005 Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci USA 102 16275 16280
26. GemsDMcElweeJJ 2005 Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech Ageing Dev 126 381 387
27. ChakrapaniBPSKumarSSubramaniamJR 2008 Development and evaluation of an in vivo assay in Caenorhabditis elegans for screening of compounds for their effect on cytochrome P450 expression. J Biosci 33 269 277
28. McEwanDLKirienkoNVAusubelFM 2012 Host Translational Inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an Immune Response in Caenorhabditis elegans. Cell Host Microbe 11 364 374
29. DunbarTLYanZBallaKMSmelkinsonMGTroemelER 2012 C. elegans Detects Pathogen-Induced Translational Inhibition to Activate Immune Signaling. Cell Host Microbe 11 375 386
30. BoucherHWTalbotGHBradleyJSEdwardsJEGilbertD 2009 Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48 1 12
31. BumannD 2008 Has nature already identified all useful antibacterial targets? Curr Opin Microbiol 11 387 392
32. HancockREWNijnikAPhilpottDJ 2012 Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10 243 254
33. HennessyEJParkerAEO'NeillLAJ 2010 Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9 293 307
34. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94
35. BeananMJStromeS 1992 Characterization of a germ-line proliferation mutation in C. elegans. Development 116 755 766
36. GoldsteinPMagnanoL 1988 Effects of dimethyl sulphoxide on early gametogenesis in Caenorhabditis elegans: ultrastructural aberrations and loss of synaptonemal complexes from pachytene nuclei. Cytobios 56 45 57
37. RandJBJohnsonCD 1995 Genetic pharmacology: interactions between drugs and gene products in Caenorhabditis elegans. EpsteinHFShakesDC 187 204 Caenorhabditis elegans: Modern Biological Analysis of an Organism. San Diego: Academic Press Inc., Vol. 48.
38. StiernagleT 1999 Maintenance of C. elegans. HopeIA 59 60 C. elegans: a practical approach. Oxford University Press, USA.
39. ReichMLiefeldTGouldJLernerJTamayoP 2006 GenePattern 2.0. Nat Genet 38 500 501
40. RichardsonCEKooistraTKimDH 2010 An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463 1092 1095
41. PfafflMW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29 e45
42. O'RourkeEJConeryALMoyTI 2009 Whole-animal high-throughput screens: the C. elegans model. Methods Mol Biol 486 57 75
43. KirienkoNVMcEnerneyJDKFayDS 2008 Coordinated regulation of intestinal functions in C. elegans by LIN-35/Rb and SLR-2 PLoS Genet 4 e1000059 doi:10.1371/journal.pgen.1000059
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 6
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