Muramylpeptide shedding modulates cell sensing of Shigella flexneri

Authors

  • Giulia Nigro,

    1. Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
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  • Luigi Lembo Fazio,

    1. Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
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  • Maria Celeste Martino,

    1. Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
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  • Giacomo Rossi,

    1. Facoltà di Medicina Veterinaria, Università di Camerino, 62024 Matelica, MC, Italy.
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  • Ivan Tattoli,

    1. Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
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    • Present address: University of Toronto, Toronto, Canada.

  • Valeria Liparoti,

    1. Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, I-80126, Napoli, Italy.
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  • Cristina De Castro,

    1. Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, I-80126, Napoli, Italy.
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  • Antonio Molinaro,

    1. Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, I-80126, Napoli, Italy.
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  • Dana J. Philpott,

    1. Groupe d'Immunité Innée et Signalisation, Institut Pasteur, 75724 Paris Cedex 15, France.
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    • Present address: University of Toronto, Toronto, Canada.

  • Maria Lina Bernardini

    Corresponding author
    1. Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
    2. Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza-Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
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*E-mail marialina.bernardini@uniroma1.it; Tel. (+39) 6 49917850; Fax (+39) 6 49917594.

Summary

Bacterial infections trigger the activation of innate immunity through the interaction of pathogen-associated molecular patterns (PAMPs) with pattern recognition molecules (PRMs). The nucleotide-binding oligomerization domain (Nod) proteins are intracellular PRMs that recognize muramylpeptides contained in peptidoglycan (PGN) of bacteria. It is still unclear how Nod1 physically interacts with PGN, a structure internal to the Gram-negative bacterial envelope. To contribute to the understanding of this process, we demonstrate that, like Escherichia coli, Bordetella pertussis and Neisseria gonorrheae, the Gram-negative pathogen Shigella spontaneously releases PGN fragments and that this process can be increased by inactivating either ampG or mppA, genes involved in PGN recycling. Both Shigella mutants, but especially the strain carrying the mppA deletion, trigger Nod1-mediated NF-κB activation to a greater extent than the wild-type strain. Likewise, muramylpeptides spontaneously shed by Shigella are able per se to trigger a Nod1-mediated response consistent with the relative amount. Finally, we found that qualitative changes in muramylpeptide shedding can alter in vivo host responses to Shigella infection. Our findings support the idea that muramylpeptides released by pathogens during infection could modulate the immune response through Nod proteins and thereby influence the outcome of disease.

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