A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system

  1. Ivo G. Bonecaa,b,
  2. Olivier Dussurgetc,d,e,
  3. Didier Cabanesc,d,e,f,
  4. Marie-Anne Nahoric,d,e,
  5. Sandra Sousac,d,e,f,
  6. Marc Lecuitc,d,e,
  7. Emmanuel Psylinakisg,h,
  8. Vassilis Bouriotisg,h,
  9. Jean-Pierre Hugoti,j,
  10. Marco Giovanninik,l,
  11. Anthony Coylem,n,
  12. John Bertinm,o,
  13. Abdelkader Namanep,
  14. Jean-Claude Roussellep,
  15. Nadège Cayetq,
  16. Marie-Christine Prévostq,
  17. Viviane Balloyr,s,
  18. Michel Chignardr,s,
  19. Dana J. Philpottt,u,
  20. Pascale Cossartb,c,d,e, and
  21. Stephen E. Girardinv,w,x
  1. aUnité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, 75724 Paris, France;
  2. cUnité des Interactions Bactéries–Cellules, Institut Pasteur, 75015 Paris, France;
  3. pPlateforme de Protéomique, Institut Pasteur, 75724 Paris, France;
  4. dInstitut National de la Santé et de la Recherche Médicale (INSERM) U604, Institut Pasteur, 75724 Paris, France;
  5. eInstitut National de la Recherche Agronomique (INRA) USC2020, Institut Pasteur, 75724 Paris, France;
  6. qPlateforme de Microscopie Électronique, Institut Pasteur, 75724 Paris, France;
  7. rUnité Défense Innée et Inflammation, Institut Pasteur, 75015 Paris, France;
  8. sINSERM E336, Institut Pasteur, 75015 Paris, France;
  9. tGroupe Immunité Innée et Signalisation, Institut Pasteur, 75724 Paris, France;
  10. vUnité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris, France;
  11. wINSERM U389 and Groupe INSERM Avenir “Peptidoglycan and Innate Immunity,” Institut Pasteur, 75724 Paris, France;
  12. gDepartment of Biology, Enzyme Biotechnology Group, University of Crete, 71409 Heraklion, Greece;
  13. hInstitute of Molecular Biology and Biotechnology, 71110 Heraklion, Greece;
  14. iDepartment of Paediatric Gastroenterology, Hôpital Robert Debré, 75935 Paris, France;
  15. jINSERM U458, F-75019 Paris, France;
  16. kGénomique Fonctionnelles des Tumeurs Solides, Fondation Jean Dausset–Centre d'Étude du Polymorphisme Humain, 75010 Paris, France;
  17. lINSERM U674, F-75010 Paris, France; and
  18. mMillennium Pharmaceuticals, Cambridge, MA 02139

  1. Edited by Stanley Falkow, Stanford University, Stanford, CA, and approved November 29, 2006

Abstract

Listeria monocytogenes is a human intracellular pathogen that is able to survive in the gastrointestinal environment and replicate in macrophages, thus bypassing the early innate immune defenses. Peptidoglycan (PG) is an essential component of the bacterial cell wall readily exposed to the host and, thus, an important target for the innate immune system. Characterization of the PG from L. monocytogenes demonstrated deacetylation of N-acetylglucosamine residues. We identified a PG N-deacetylase gene, pgdA, in L. monocytogenes genome sequence. Inactivation of pgdA revealed the key role of this PG modification in bacterial virulence because the mutant was extremely sensitive to the bacteriolytic activity of lysozyme, and growth was severely impaired after oral and i.v. inoculations. Within macrophage vacuoles, the mutant was rapidly destroyed and induced a massive IFN-β response in a TLR2 and Nod1-dependent manner. Together, these results reveal that PG N-deacetylation is a highly efficient mechanism used by Listeria to evade innate host defenses. The presence of deacetylase genes in other pathogenic bacteria indicates that PG N-deacetylation could be a general mechanism used by bacteria to evade the host innate immune system.

Footnotes

  • bTo whom correspondence may be addressed. E-mail: bonecai{at}pasteur.fr or pcossart{at}pasteur.fr

  • Author contributions: I.G.B., O.D., and S.E.G. designed research; I.G.B., O.D., D.C., M.-A.N., S.S., M.L., J.-C.R., N.C., and S.E.G. performed research; I.G.B., E.P., V. Bouriotis, J.-P.H., M.G., A.C., J.B., V. Balloy, and M.C. contributed new reagents/analytic tools; I.G.B., O.D., M.L., A.N., M.-C.P., D.J.P., P.C., and S.E.G. analyzed data; and I.G.B. and P.C. wrote the paper.

  • ↵ fPresent address: Group of Molecular Microbiology, Instituto de Biologia Celular e Molecular, 4150-180 Porto, Portugal.

  • ↵ nPresent Address: Medimmune, Gaithersburg, MD 20878.

  • ↵ oPresent Address: Synta Pharmaceuticals, Lexington, MA 02421.

  • ↵ uPresent address: Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 2E4.

  • ↵ xPresent address: Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada M5S 2E4.

  • The authors declare no conflict of interest.

  • This article is a PNAS direct submission.

  • See Commentary 691.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0609672104/DC1.

  • Abbreviations:
    PEM,
    peritoneal macrophage;
    PG,
    peptidoglycan.

  • Freely available online through the PNAS open access option.

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  1. Published online before print January 10, 2007, doi: 10.1073/pnas.0609672104 PNAS January 16, 2007 vol. 104 no. 3 997-1002
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