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MisR/MisS Two-Component Regulon in Neisseria meningitidis ^,

Yih-Ling Tzeng,^1* Charlene M. Kahler,³ Xinjian Zhang,^1, and David S. Stephens^1,2

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia,¹ Laboratories of Bacterial Pathogenesis, Department of Veterans Affairs Medical Center, Decatur, Georgia,² Discipline of Microbiology and Immunology, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia³

Received 23 July 2007/ Returned for modification 6 September 2007/ Accepted 20 November 2007

Two-component regulatory systems are involved in processes important for bacterial pathogenesis. Inactivation of the misR/misS system in Neisseria meningitidis results in the loss of phosphorylation of the lipooligosaccharide inner core and causes attenuation in a mouse model of meningococcal infection. One hundred seventeen (78 up-regulated and 39 down-regulated) potential regulatory targets of the MisR/MisS (MisR/S) system were identified by transcriptional profiling of the NMBmisR mutant and the parental wild-type meningococcal strain NMB. The regulatory effect was further confirmed in a subset of target genes by quantitative real-time PCR and β-galactosidase transcriptional fusion reporter assays. The MisR regulon includes genes encoding proteins necessary for protein folding in the bacterial cytoplasm and periplasm, transcriptional regulation, metabolism, iron assimilation, and type I protein transport. Mutation in the MisR/S system caused increased sensitivity to oxidative stress and also resulted in decreased susceptibility to complement-mediated killing by normal human serum. To identify the direct targets of MisR regulation, electrophoretic mobility shift assays were carried out using purified MisR-His₆ protein. Among 22 genes examined, misR directly interacted with 14 promoter regions. Six promoters were further investigated by DNase I protection assays, and a MisR-binding consensus sequence was proposed. Thus, the direct regulatory targets of MisR and the minimal regulon of the meningococcal MisR/S two-component signal transduction system were characterized. These data indicate that the MisR/S system influences a wide range of biological functions in N. meningitidis either directly or via intermediate regulators.

Published ahead of print on 3 December 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: V. J. DiRita

Present address: Department of Chemistry, Georgia State University, Atlanta, GA.