INSERM U643, Nantes, CHU de Nantes, IUN, Nantes, Université de Nantes, UMR 643, Nantes, France.
PLoS One. 2011;6(10):e23995. doi: 10.1371/journal.pone.0023995. Epub 2011 Oct 27.
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.
脑膜炎奈瑟菌是一种人类病原体，可导致危及生命的炎症性疾病。脑膜炎球菌青霉素结合蛋白（PBP），尤其是 PBP2，参与了细菌对β-内酰胺类抗生素的耐药性。在这里，我们描述了 PBP2 的一个新功能，即它以时间和剂量依赖的方式激活人和小鼠树突状细胞（DC）。PBP2 诱导 MHC II（LOGEC50=4.7μg/ml±0.1）、CD80（LOGEC50=4.88μg/ml±0.15）和 CD86（LOGEC50=5.36μg/ml±0.1）的表达。当 DC 与抗 PBP2 抗体共同处理时，这种作用被消除。PBP2 处理的 DC 在体外和体内显示出增强的免疫原性。此外，与 PBP2 共纯化的蛋白对 DC 成熟没有影响。我们通过不同的体内和体外方法表明，这种效应不是由于内毒素污染所致。在机制水平上，PBP2 诱导核内定位的 p65 NF-kB 为 70.7±5.1%的细胞，而未经处理的 DC 中为 12±2.6%，并且需要 TLR4 表达来成熟 DC。免疫沉淀和阻断实验表明 PBP2 结合 TLR4。总之，我们描述了脑膜炎奈瑟菌 PBP2 的一个新功能，即作为宿主-病原体界面的病原体相关分子模式（PAMP），可以被免疫系统识别为危险信号，促进免疫反应的发展。
