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Autophagic control of listeria through intracellular innate immune recognition in drosophila

Abstract

Autophagy, an evolutionally conserved homeostatic process for catabolizing cytoplasmic components, has been linked to the elimination of intracellular pathogens during mammalian innate immune responses. However, the mechanisms underlying cytoplasmic infection-induced autophagy and the function of autophagy in host survival after infection with intracellular pathogens remain unknown. Here we report that in drosophila, recognition of diaminopimelic acid–type peptidoglycan by the pattern-recognition receptor PGRP-LE was crucial for the induction of autophagy and that autophagy prevented the intracellular growth of Listeria monocytogenes and promoted host survival after this infection. Autophagy induction occurred independently of the Toll and IMD innate signaling pathways. Our findings define a pathway leading from the intracellular pattern-recognition receptors to the induction of autophagy to host defense.

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Figure 1: PGRP-LE in hemocytes is essential for resistance to L. monocytogenes infection in vivo.
Figure 2: PGRP-LE and autophagy, but not the Toll and IMD pathways, are needed to suppress the intracellular growth of L. monocytogenes in hemocytes.
Figure 3: Autophagy is crucial for host survival after L. monocytogenes infection.
Figure 4: Autophagy, but not the IMD or Toll pathway, is crucial for PGRP-LE-mediated suppression of the intracellular growth of L. monocytogenes in S2 cells.
Figure 5: PGRP-LE mediates autophagosome formation in S2 cells and hemocytes.
Figure 6: PGRP-LE is responsible for autophagy induced by TCT and DAP-type PGN.

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References

  1. Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Ferrandon, D., Imler, J.-L., Hetru, C. & Hoffmann, J.A. The Drosophila systemic immune response: sensing and signaling during bacterial and fungal infections. Nat. Rev. Immunol. 7, 862–874 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Takehana, A. et al. Peptidoglycan recognition protein (PGRP)-LE and PGRP-LC act synergistically in Drosophila immunity. EMBO J. 23, 4690–4700 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Takehana, A. et al. Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and the prophenoloxidase cascade in Drosophila larvae. Proc. Natl. Acad. Sci. USA 99, 13705–13710 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kaneko, T. et al. PGRP-LC and PGRP-LE have essential yet distinct functions in the drosophila immune response to monomeric DAP-type peptidoglycan. Nat. Immunol. 7, 715–723 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Lemaitre, B., Reichhart, J.-M. & Hoffmann, J.A. Drosophila host defense: Differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc. Natl. Acad. Sci. USA 94, 14614–14619 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kanneganti, T.-D., Lamkanfi, M. & Núñez, G. Intracellular NOD-like receptor in host defense and disease. Immunity 27, 549–559 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Chaput, C. & Boneca, I.G. Peptidoglycan detection by mammals and flies. Microbes Infect. 9, 637–647 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Delbridge, L.M. & O'Riordan, M.X.D. Innate recognition of intracellular bacteria. Curr. Opin. Immunol. 19, 10–16 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Hsu, Y.M. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat. Immunol. 8, 198–205 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat. Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nakagawa, I. et al. Autophagy defends cells against invading Group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Gutierrez, M.G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Ling, Y.M. et al. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J. Exp. Med. 203, 2063–2071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Andrade, R.M., Weaaendarp, M., Gubbels, M.-J., Striepen, B. & Subauste, C.S. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116, 2366–2377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Singh, S.B., Davis, A.S., Taylor, G.A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Xu, Y. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135–144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Delgado, M.A., Elmaoued, R.A., Davis, A.S., Kyei, G. & Deretic, V. Toll-like receptors control autophagy. EMBO J. 27, 1110–1121 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sanjuan, M.A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253–1257 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Mansfield, B.E., Dionne, M.S., Schneider, D.S. & Freitag, N.E. Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster. Cell. Microbiol. 5, 901–911 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Hamon, M., Bierne, H. & Cossart, P. Listeria monocytogenes: a multifaceted model. Nat. Rev. Microbiol. 4, 423–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Jones, S. & Portnoy, D.A. Characterization of Listeria monocytogenes pathogenesis in a strain expressing perfringolysin O in place of listeriolysin O. Infect. Immun. 62, 5608–5613 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Goto, A. Kadowaki, T. and Kitagawa, Y. Drosophila hemolectin gene is expressed in embryonic and larval hemocytes and its knock down causes bleeding defects. Dev. Biol. 264, 582–591 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Scott, R.C., Schuldiner, O. & Neufeld, T.P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Rusten, T.E. et al. Programmed autophagy in the Drosophila fat body is induced by ecdysome through regulation of the PI3K pathway. Dev. Cell 7, 179–192 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Py, B.F., Lipinski, M.M. & Yuan, J. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3, 117–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Scott, R.C., Juhasz, G. & Neufeld, T.P. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr. Biol. 17, 1–11 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheng, L.W. & Portnoy, D.A. Drosophila S2 cells: an alternative infection model for Listeria monocytogenes. Cell. Microbiol. 5, 875–885 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Agaisse, H. et al. Genome-wide RNAi screen for host factors required for intracellular bacterial infection. Science 309, 1248–1251 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaneko, T. et al. Monomeric and polymeric gram-negative peptidoglycan but not purified LPS stimulate the Drosophila IMD pathway. Immunity 20, 637–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Kitaura, Y. et al. N2-(-D-glutamyl)-meso-2L,2′D-diaminopimelic acid as the minimal prerequisite structure of FK-156: its acyl derivatives with potent immunostimulating activity. J. Med. Chem. 25, 335–337 (1982).

    Article  CAS  PubMed  Google Scholar 

  37. Sun, X., Yin, J., Starovansnik, M.A., Fairbrother, W.J. & Dixit, V.M. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J. Biol. Chem. 277, 9505–9511 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activation. Nat. Immunol. 5, 503–507 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Gottar, M. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Kotani, S., Watanabe, Y., Shimono, T., Kinoshita, F. & Narita, T. Immunoadjuvant activities of peptidoglycan subunits from the cell walls of Staphylococcus aureus and Lactobacillus plantarum. Biken J. 18, 93–103 (1975).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D.A. Portnoy (University of California, Berkeley) and D.E. Higgins (Harvard Medical School) for L. monocytogenes strains; L.W. Cheng (University of California, Berkeley) for the S2 cell L. monocytogenes infection protocol; T.P. Neufeld (University of Minnesota) for Atg1Δ3D, Atg5IR, Atg1 and GFP-LC3; D. Hultmark (Umeå University) for RelishE20; K. Anderson (Cornell University) for PGRP-LC7454; A. Goto (Tohoku University) for hml-Gal4; the Bloomington Stock Center, Drosophila Genetic Resource Center at the Kyoto Institute of Technology and the Genetic Strain Research Center of National Institute of Genetics for fly stocks; and S. Iwanaga, M. Mitsuyama, A. Yamamoto and S. Natori for discussions. Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Japan Society for the Promotion of Science; the Program for the Promotion of Basic Research Activities for Innovative Biosciences; the National Institutes of Health (AI60025 and AI074958 to N.S.; AI074958); and the Naito Foundation.

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Yano, T., Mita, S., Ohmori, H. et al. Autophagic control of listeria through intracellular innate immune recognition in drosophila. Nat Immunol 9, 908–916 (2008). https://doi.org/10.1038/ni.1634

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