title: Penicillin binding proteins as danger signals: meningococcal penicillin binding protein 2 activates dendritic cells through Toll-like receptor 4.
abstract: Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 µg/ml ± 0.1), CD80 (LOGEC50 = 4.88 µg/ml ± 0.15) and CD86 (LOGEC50 = 5.36 µg/ml ± 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 ± 5.1% cells versus 12 ± 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed thatPBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
authors: INSERM U643, Nantes, CHU de Nantes, IUN, Nantes, Université de Nantes, UMR 643, Nantes, France.
authors: Marcelo
authors: M
authors: Hill
authors: Ala-Eddine
authors: AE
authors: Deghmane
authors: Mercedes
authors: M
authors: Segovia
authors: Maria Leticia
authors: ML
authors: Zarantonelli
authors: Gaëlle
authors: G
authors: Tilly
authors: Philippe
authors: P
authors: Blancou
authors: Gaëlle
authors: G
authors: Bériou
authors: Régis
authors: R
authors: Josien
authors: Ignacio
authors: I
authors: Anegon
authors: Eva
authors: E
authors: Hong
authors: Corinne
authors: C
authors: Ruckly
authors: Aude
authors: A
authors: Antignac
authors: Meriem
authors: M
authors: El Ghachi
authors: Ivo Gomperts
authors: IG
authors: Boneca
authors: Muhamed-Kheir
authors: MK
authors: Taha
authors: Maria Cristina
authors: MC
authors: Cuturi
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D051379:Mice; D009345:Neisseria meningitidis / Q000737:chemistry / Q000276:immunology*; D046915:Penicillin-Binding Proteins / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D046915:Penicillin-Binding Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4