Phosphoryl Moieties of Lipid A from Neisseria meningitidis and N. gonorrhoeae Lipooligosaccharides Play an Important Role in Activation of Both MyD88-and TRIF-Dependent TLR4-MD-2 Signaling Pathways

We have previously shown that the lipooligosaccharide (LOS) from Neisseria meningitidis and N. gonorrhoeae engages the TLR4-MD-2 complex. In this study, we report that LOS from different meningococcal and gonococcal strains have different potencies to activate NF-kappa B through TLR4-MD-2 and that the relative activation can be correlated with ion abundances in MALDI-TOF mass spectrometry that are indicative of the number of phosphoryl substituents on the lipid A (LA) component of the LOS. The LOSs from three of the strains, meningococcal strain 89I and gonococcal strains 1291 and GC56, representing high, intermediate, and low potency on NF-kappa B activation, respectively, differently activated cytokine expression through the TLR4-MD-2 pathway in monocytes. In addition to induction of typical inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6, MIP-1 alpha and MIP-1 beta also were significantly higher in cells treated with 89I LOS, which had the most phosphoryl substitutions on the LA compared with 1291 LOS and GC56 LOS. We found that LOS activated both the MyD88- and TRIF-dependent pathways through NF-kappa B and IFN regulatory factor 3 transcription factors, respectively. Moreover, LOS induced the expression of costimulatory molecule CD80 on the surfaces of monocytes via upregulation of IFN regulatory factor 1. These results suggest that phosphoryl moieties of LA from N. meningitidis and N. gonorrhoeae LOSs play an important role in activation of both the MyD88-and TRIF-dependent pathways. Our findings are consistent with the concept that bacteria modulate pathogen-associated molecular patterns by expression of phosphoryl moieties on the LA to optimize interactions with the host. The Journal of Immunology, 2010, 185: 6974-6984.