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Journal of Bacteriology, September 2009, p. 5387-5397, Vol. 191, No. 17
0021-9193/09/$08.00+0     doi:10.1128/JB.00370-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CsrRS Regulates Group B Streptococcus Virulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine Development{triangledown} ,{dagger}

Isabella Santi,1 Renata Grifantini,1 Sheng-Mei Jiang,2 Cecilia Brettoni,1 Guido Grandi,1* Michael R. Wessels,2 and Marco Soriani1

Novartis Vaccines and Diagnostics Srl, Via Fiorentina 1, 53100, Siena, Italy,1 Division of Infectious Diseases, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 021152

Received 17 March 2009/ Accepted 15 June 2009

To identify factors involved in the response of group B streptococci (GBS) to environmental pH, we performed a comparative global gene expression analysis of GBS at acidic and neutral pHs. We found that the transcription of 317 genes was increased at pH 5.5 relative to that at pH 7.0, while 61 genes were downregulated. The global response to acid stress included the differential expression of genes involved in transport, metabolism, stress response, and virulence. Known vaccine candidates, such as BibA and pilus components, were also regulated by pH. We observed that many of the genes involved in the GBS response to pH are known to be controlled by the CsrRS two-component system. Comparison of the regulon of wild-type strain 2603 V/R with that of a csrRS deletion mutant strain revealed that the pH-dependent regulation of 90% of the downregulated genes and 59.3% of the up-regulated genes in strain 2603 V/R was CsrRS dependent and that many virulence factors were overexpressed at high pH. Beta-hemolysin regulation was abrogated by selective inactivation of csrS, suggesting the implication of the CsrS protein in pH sensing. These results imply that the translocation of GBS from the acidic milieu of the vagina to the neutral pH of the neonatal lung signals the up-regulation of GBS virulence factors and conversion from a colonizing to an invasive phenotype. In addition, the fact that increased exposure of BibA on the bacterial surface at pH 7.0 induced opsonophagocytic killing of GBS in immune serum highlights the importance of pH regulation in the protective efficacy of specific antibodies to surface-exposed GBS proteins.

* Corresponding author. Mailing address: Novartis Vaccines, Via Fiorentina 1, 53100, Siena, Italy. Phone: (39) 0577 243390. Fax: (39) 0577 243564. E-mail: guido.grandi{at}novartis.com

{triangledown} Published ahead of print on 19 June 2009.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

Journal of Bacteriology, September 2009, p. 5387-5397, Vol. 191, No. 17
0021-9193/09/$08.00+0     doi:10.1128/JB.00370-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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