Penicillin Binding Proteins as Danger Signals: Meningococcal Penicillin Binding Protein 2 Activates Dendritic Cells through Toll-Like Receptor 4.

Marcelo Hill (1, 2) , Ala-Eddine Deghmane (3) , Mercedes Segovia (1) , Maria Leticia Zarantonelli (3) , Gaëlle Tilly (1) , Philippe Blancou (4) , Gaëlle Bériou (1) , Régis Josien (1, 5) , Ignacio Anegon (1) , Eva Hong (3) , Corinne Ruckly (3) , Aude Antignac (3) , Meriem El Ghachi (6) , Ivo Gomperts Boneca (6) , Muhamed-Kheir Taha (3) , Maria Cristina Cuturi (1)

1 INSERM UMR 643
2 UDELAR - Universidad de la República [Montevideo]
3 Infections Bactériennes Invasives
4 IECM - Immuno-Endocrinologie Cellulaire et Moléculaire
5 CHU Nantes - Centre hospitalier universitaire de Nantes
6 BGPB - Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall

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 b-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 mg/ml60.1), CD80 (LOGEC50 = 4.88 mg/ml60.15) and CD86 (LOGEC50 = 5.36 mg/ml60.1). 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 70.765.1% cells versus 1262.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed that PBP2 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.

Domains: Bacteriology

Marcelo Hill, Ala-Eddine Deghmane, Mercedes Segovia, Maria Leticia Zarantonelli, Gaëlle Tilly, et al.. Penicillin Binding Proteins as Danger Signals: Meningococcal Penicillin Binding Protein 2 Activates Dendritic Cells through Toll-Like Receptor 4.. PLoS ONE, 2011, 6 (10), pp.e23995. ⟨10.1371/journal.pone.0023995⟩. ⟨pasteur-02093194⟩