Muramylpeptide shedding modulates cell sensing of Shigella flexneri.
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-kappaB 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.
Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
Giulia
G
Nigro
Luigi Lembo
LL
Fazio
Maria Celeste
MC
Martino
Giacomo
G
Rossi
Ivan
I
Tattoli
Valeria
V
Liparoti
Cristina
C
De Castro
Antonio
A
Molinaro
Dana J
DJ
Philpott
Maria Lina
ML
Bernardini
D000818:Animals; D019677:Artificial Gene Fusion; D001426:Bacterial Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D004405:Dysentery, Bacillary; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000382:microbiology / Q000473:pathology; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000382:microbiology / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism*; D012763:Shigella flexneri / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000382:microbiology / Q000473:pathology
C084284:AmpG protein, Bacteria; D001426:Bacterial Proteins; D002352:Carrier Proteins; D016207:Cytokines; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D049409:Luciferases, Firefly