title: The MisR/MisS two-component regulatory system influences inner core structure and immunotype of lipooligosaccharide in Neisseria meningitidis.
abstract: Lipooligosaccharide (LOS) of Neisseria meningitidis is the major inflammatory mediator that contributes to meningococcal pathogenesis. Variable attachments to the HepII residue of the LOS inner core together with the alpha-chain heterogeneity result in immunologically distinct LOS structures, which may be selected for during human infection. Lpt-3, a phosphoethanolamine (PEA) transferase, and LgtG, a glucosyltransferase, mediate the substitution of PEA or glucose at the O-3 position of HepII in L3 or L2 LOS immunotypes, respectively. Inactivation of a two-component response regulator, encoded by NMB0595, in N. meningitidis strain NMB resulted in the loss of all PEA decorations on the LOS inner core expressed by the NMB0595 mutant. When compared with the parental strain NMB that predominantly expresses L2 immunotype LOS and other minor LOS structures, the NMB0595 mutant expresses a pure population of a novel LOS structure completely substituted at the HepII O-3 position with glucose, but lacking other PEA decorations on the inner core. Quantitative real time PCR experiments showed increased transcription of lgtG in the NMB0595 mutant, and no significant change in lpt-3 transcription. Inactivation of lgtG resulted in LOS inner cores without glucose, but these structures, even though the lpt-3 transcription was unaffected, also lacked the O-3-linked PEA. Consistently, a double mutation of lgtG and misR in strain NMB yielded a LOS structure without PEA or Glc substitution of HepII. These data indicated a new pathway for the regulation of LOS inner core structure in N. meningitidis through an environmental sensing two-component regulatory system, named misR(NMB0595)/misS(NMB0594) for regulator and sensor of the meningococcal inner core structure.
authors.affiliation: Department of Medicine, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA. ytzeng@emory.edu
authors.forename: Yih-Ling
authors.initials: YL
authors.lastname: Tzeng
authors.forename: Anup
authors.initials: A
authors.lastname: Datta
authors.forename: Karita
authors.initials: K
authors.lastname: Ambrose
authors.forename: Miranda
authors.initials: M
authors.lastname: Lo
authors.forename: John K
authors.initials: JK
authors.lastname: Davies
authors.forename: Russell W
authors.initials: RW
authors.lastname: Carlson
authors.forename: David S
authors.initials: DS
authors.lastname: Stephens
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Kahler
mesh_terms: D015139:Blotting, Southern; D002240:Carbohydrate Sequence; D004247:DNA / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004983:Ethanolamines / Q000737:chemistry; D005964:Glucosyltransferases / Q000378:metabolism; D000071677:Histidine Kinase; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009345:Neisseria meningitidis / Q000378:metabolism*; D009844:Oligosaccharides / Q000737:chemistry; D011112:Polymyxin B / Q000737:chemistry; D011485:Protein Binding; D011494:Protein Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014158:Transcription, Genetic
chemical_list: D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D004983:Ethanolamines; D008070:Lipopolysaccharides; D009844:Oligosaccharides; C023023:lipid-linked oligosaccharides; C005448:phosphorylethanolamine; D004247:DNA; D005964:Glucosyltransferases; D011494:Protein Kinases; D000071677:Histidine Kinase; D011112:Polymyxin B