title: Lack of lipid A pyrophosphorylation and functional lptA reduces inflammation by Neisseria commensals.
abstract: The interaction of the immune system with Neisseria commensals remains poorly understood. We have previously shown that phosphoethanolamine on the lipid A portion of lipooligosaccharide (LOS) plays an important role in Toll-like receptor 4 (TLR4) signaling. For pathogenic Neisseria, phosphoethanolamine is added to lipid A by the phosphoethanolamine transferase specific for lipid A, which is encoded by lptA. Here, we report that Southern hybridizations and bioinformatics analyses of genomic sequences from all eight commensal Neisseria species confirmed that lptA was absent in 15 of 17 strains examined but was present in N. lactamica. Mass spectrometry of lipid A and intact LOS revealed the lack of both pyrophosphorylation and phosphoethanolaminylation in lipid A of commensal species lacking lptA. Inflammatory signaling in human THP-1 monocytic cells was much greater with pathogenic than with commensal Neisseria strains that lacked lptA, and greater sensitivity to polymyxin B was consistent with the absence of phosphoethanolamine. Unlike the other commensals, whole bacteria of two N. lactamica commensal strains had low inflammatory potential, whereas their lipid A had high-level pyrophosphorylation and phosphoethanolaminylation and induced high-level inflammatory signaling, supporting previous studies indicating that this species uses mechanisms other than altering lipid A to support commensalism. A meningococcal lptA deletion mutant had reduced inflammatory potential, further illustrating the importance of lipid A pyrophosphorylation and phosphoethanolaminylation in the bioactivity of LOS. Overall, our results indicate that lack of pyrophosphorylation and phosphoethanolaminylation of lipid A contributes to the immune privilege of most commensal Neisseria strains by reducing the inflammatory potential of LOS.
authors.affiliation: Center for Immunochemistry, Veterans Affairs Medical Center, San Francisco, California, USA.
authors.forename: Constance M
authors.initials: CM
authors.lastname: John
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Liu
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Phillips
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Yang
authors.forename: Courtney R
authors.initials: CR
authors.lastname: Funk
authors.forename: Lindsey I
authors.initials: LI
authors.lastname: Zimmerman
authors.forename: J McLeod
authors.initials: JM
authors.lastname: Griffiss
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Stein
authors.forename: Gary A
authors.initials: GA
authors.lastname: Jarvis
mesh_terms: D015139:Blotting, Southern; D002478:Cells, Cultured; D019295:Computational Biology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008050:Lipid A / Q000276:immunology / Q000378:metabolism*; D009343:Neisseria / Q000276:immunology* / Q000472:pathogenicity; D010766:Phosphorylation; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry
chemical_list: D008050:Lipid A