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J. Biol. Chem., Vol. 279, Issue 33, 35053-35062, August 13, 2004

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The MisR/MisS Two-component Regulatory System Influences Inner Core Structure and Immunotype of Lipooligosaccharide in Neisseria meningitidis^*

Yih-Ling Tzeng¶, Anup Datta||, Karita Ambrose**, Miranda Lo, John K. Davies, Russell W. Carlson||, David S. Stephens**, and Charlene M. Kahler

From the Departments of Medicine and ^**Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, the Veterans Affairs Medical Center, Decatur, Georgia 30033, the Department of Microbiology, Monash University, Clayton VIC3 168, Australia, and the ^||Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602

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 -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.

Received for publication, February 9, 2004 , and in revised form, May 6, 2004.

^* This work was supported by NIAID, National Institutes of Health Grant AI33517 (to D. S. S.) and Department of Energy Grant DE-FG-02-93ER20097 (to the Complex Carbohydrate Research Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Wyeth, 401 N. Middletown Rd., Pearl River, NY.

^¶ To whom correspondence should be addressed: Woodruff Memorial Bldg., Rm. 2107, 1639 Pierce Dr., Atlanta, GA 30322. Tel.: 404-712-2055; Fax: 404-712-2278; E-mail: ytzeng{at}emory.edu.

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