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Journal of Bacteriology, April 2009, p. 2023-2032, Vol. 191, No. 7
0021-9193/09/$08.00+0     doi:10.1128/JB.01216-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The CiaR Response Regulator in Group B Streptococcus Promotes Intracellular Survival and Resistance to Innate Immune Defenses {triangledown}

Darin Quach,1 Nina M. van Sorge,2 Sascha A. Kristian,2 Joshua D. Bryan,3 Daniel W. Shelver,3 and Kelly S. Doran1,2*

Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, California 92182,1 Department of Pediatrics, Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California 92093,2 Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 711303

Received 29 August 2008/ Accepted 23 December 2008

Group B Streptococcus (GBS) is major cause of invasive disease in newborn infants and the leading cause of neonatal meningitis. To gain access to the central nervous system (CNS), GBS must not only subvert host defenses in the bloodstream but also invade and survive within brain microvascular endothelial cells (BMEC), the principal cell layer composing the blood-brain barrier (BBB). While several GBS determinants that contribute to the invasion of BMEC have been identified, little is known about the GBS factors that are required for intracellular survival and ultimate disease progression. In this study we sought to identify these factors by screening a random GBS mutant library in an in vitro survival assay. One mutant was identified which contained a disruption in a two-component regulatory system homologous to CiaR/CiaH, which is present in other streptococcal pathogens. Deletion of the putative response regulator, ciaR, in GBS resulted in a significant decrease in intracellular survival within neutrophils, murine macrophages, and human BMEC, which was linked to increased susceptibility to killing by antimicrobial peptides, lysozyme, and reactive oxygen species. Furthermore, competition experiments with mice showed that wild-type GBS had a significant survival advantage over the GBS {Delta}ciaR mutant in the bloodstream and brain. Microarray analysis comparing gene expression between wild-type and {Delta}ciaR mutant GBS bacteria revealed several CiaR-regulated genes that may contribute to stress tolerance and the subversion of host defenses by GBS. Our results identify the GBS CiaR response regulator as a crucial factor in GBS intracellular survival and invasive disease pathogenesis.

* Corresponding author. Mailing address: Department of Biology and Center for Microbial Sciences, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182. Phone: (619) 594-1867. Fax: (619) 594-5676. E-mail: kdoran{at}sciences.sdsu.edu

{triangledown} Published ahead of print on 29 December 2008.

Journal of Bacteriology, April 2009, p. 2023-2032, Vol. 191, No. 7
0021-9193/09/$08.00+0     doi:10.1128/JB.01216-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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