Pseudomonas Aeruginosa Suppresses Host Immunity by Activating the DAF-2 Insulin-like Signaling Pathway in Caenorhabditis Elegans

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2008 Oct 18

PMID 18927620

Citations 118

Authors

Eric A Evans

Trupti Kawli

Man-Wah Tan

Affiliations

Soon will be listed here.

Abstract

Some pathogens have evolved mechanisms to overcome host immune defenses by inhibiting host defense signaling pathways and suppressing the expression of host defense effectors. We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin-like signaling pathway. The DAF-2/DAF-16 pathway is important for the regulation of many aspects of organismal physiology, including metabolism, stress response, longevity, and immune function. We show that intestinal expression of DAF-16 is required for resistance to P. aeruginosa and that the suppression of immune defense genes is dependent on the insulin-like receptor DAF-2 and the FOXO transcription factor DAF-16. By visualizing the subcellular localization of DAF-16::GFP fusion protein in live animals during infection, we show that P. aeruginosa-mediated downregulation of a subset of immune genes is associated with the ability to translocate DAF-16 from the nuclei of intestinal cells. Suppression of DAF-16 is mediated by an insulin-like peptide, INS-7, which functions upstream of DAF-2. Both the inhibition of DAF-16 and downregulation of DAF-16-regulated genes, such as thn-2, lys-7, and spp-1, require the P. aeruginosa two-component response regulator GacA and the quorum-sensing regulators LasR and RhlR and are not observed during infection with Salmonella typhimurium or Enterococcus faecalis. Our results reveal a new mechanism by which P. aeruginosa suppresses host immune defense.

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References

Rahme L, Tan M, Le L, Wong S, Tompkins R, Calderwood S . Use of model plant hosts to identify Pseudomonas aeruginosa virulence factors. Proc Natl Acad Sci U S A. 1997; 94(24):13245-50. PMC: 24294. DOI: 10.1073/pnas.94.24.13245. View

Paradis S, Ruvkun G . Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 1998; 12(16):2488-98. PMC: 317081. DOI: 10.1101/gad.12.16.2488. View

Tan M, Ausubel F . Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci U S A. 1999; 96(2):715-20. PMC: 15202. DOI: 10.1073/pnas.96.2.715. View

Banyai L, Patthy L . Amoebapore homologs of Caenorhabditis elegans. Biochim Biophys Acta. 1999; 1429(1):259-64. DOI: 10.1016/s0167-4838(98)00237-4. View

Kopp E, Medzhitov R . The Toll-receptor family and control of innate immunity. Curr Opin Immunol. 1999; 11(1):13-8. DOI: 10.1016/s0952-7915(99)80003-x. View

Tan M, Rahme L, Sternberg J, Tompkins R, Ausubel F . Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors. Proc Natl Acad Sci U S A. 1999; 96(5):2408-13. PMC: 26797. DOI: 10.1073/pnas.96.5.2408. View

Hsin H, Kenyon C . Signals from the reproductive system regulate the lifespan of C. elegans. Nature. 1999; 399(6734):362-6. DOI: 10.1038/20694. View

Paradis S, Ailion M, Toker A, Thomas J, Ruvkun G . A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev. 1999; 13(11):1438-52. PMC: 316759. DOI: 10.1101/gad.13.11.1438. View

Ailion M, Inoue T, Weaver C, Holdcraft R, Thomas J . Neurosecretory control of aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1999; 96(13):7394-7. PMC: 22096. DOI: 10.1073/pnas.96.13.7394. View

10.

Honda Y, Honda S . The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 1999; 13(11):1385-93. View

11.

Lau G, Hassett D, Ran H, Kong F . The role of pyocyanin in Pseudomonas aeruginosa infection. Trends Mol Med. 2004; 10(12):599-606. DOI: 10.1016/j.molmed.2004.10.002. View

12.

Wareham D, Papakonstantinopoulou A, Curtis M . The Pseudomonas aeruginosa PA14 type III secretion system is expressed but not essential to virulence in the Caenorhabditis elegans-P. aeruginosa pathogenicity model. FEMS Microbiol Lett. 2004; 242(2):209-16. DOI: 10.1016/j.femsle.2004.11.018. View

13.

Mochii M, Yoshida S, Morita K, Kohara Y, Ueno N . Identification of transforming growth factor-beta- regulated genes in caenorhabditis elegans by differential hybridization of arrayed cDNAs. Proc Natl Acad Sci U S A. 1999; 96(26):15020-5. PMC: 24766. DOI: 10.1073/pnas.96.26.15020. View

14.

Apfeld J, Kenyon C . Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature. 2000; 402(6763):804-9. DOI: 10.1038/45544. View

15.

Anderson K . Toll signaling pathways in the innate immune response. Curr Opin Immunol. 2000; 12(1):13-9. DOI: 10.1016/s0952-7915(99)00045-x. View

16.

Rahme L, Ausubel F, Cao H, Drenkard E, Goumnerov B, Lau G . Plants and animals share functionally common bacterial virulence factors. Proc Natl Acad Sci U S A. 2000; 97(16):8815-21. PMC: 34017. DOI: 10.1073/pnas.97.16.8815. View

17.

Furuyama T, Nakazawa T, Nakano I, Mori N . Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J. 2000; 349(Pt 2):629-34. PMC: 1221187. DOI: 10.1042/0264-6021:3490629. View

18.

Pierce S, Costa M, Wisotzkey R, Devadhar S, Homburger S, Buchman A . Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 2001; 15(6):672-86. PMC: 312654. DOI: 10.1101/gad.867301. View

19.

Lin K, Hsin H, Libina N, Kenyon C . Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001; 28(2):139-45. DOI: 10.1038/88850. View

20.

Staskawicz B, Mudgett M, Dangl J, Galan J . Common and contrasting themes of plant and animal diseases. Science. 2001; 292(5525):2285-9. DOI: 10.1126/science.1062013. View