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Infection and Immunity, September 2005, p. 5743-5753, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5743-5753.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Characterization of MtsR, a New Metal Regulator in Group A Streptococcus, Involved in Iron Acquisition and Virulence

Christopher S. Bates,1,{dagger} Chadia Toukoki,1,{dagger} Melody N. Neely,2 and Zehava Eichenbaum1*

Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, Georgia 30303,1 Department of Microbiology and Immunology, Wayne State School of Medicine, 540 East Canfield Ave., Detroit, Michigan 482012

Received 8 December 2004/ Returned for modification 3 February 2005/ Accepted 15 April 2005

Group A streptococcus (GAS) is a common pathogen of the human skin and mucosal surfaces capable of producing a variety of diseases. In this study, we investigated regulation of iron uptake in GAS and the role of a putative transcriptional regulator named MtsR (for Mts repressor) with homology to the DtxR family of metal-dependent regulatory proteins. An mtsR mutant was constructed in NZ131 (M49 serotype) and analyzed. Western blot and RNA analysis showed that mtsR inactivation results in constitutive transcription of the sia (streptococcal iron acquisition) operon, which was negatively regulated by iron in the parent strain. A recombinant MtsR with C-terminal His6 tag fusion (rMtsR) was cloned and purified. Electrophoretic mobility gel shift assays demonstrated that rMtsR specifically binds to the sia promoter region in an iron- and manganese-dependent manner. Together, these observations indicate that MtsR directly represses the sia operon during cell growth under conditions of high metal levels. Consistent with deregulation of iron uptake, the mtsR mutant is hypersensitive to streptonigrin and hydrogen peroxide, and 55Fe uptake assays demonstrate that it accumulates 80% ± 22.5% more iron than the wild-type strain during growth in complete medium. Studies with a zebrafish infection model revealed that the mtsR mutant is attenuated for virulence in both the intramuscular and the intraperitoneal routes. In conclusion, MtsR, a new regulatory protein in GAS, controls iron homeostasis and has a role in disease production.

* Corresponding author. Mailing address: Department of Biology, Georgia State University, P.O. Box 4010, Atlanta, GA 30302-4010. Phone: (404) 651-2930. Fax: (404) 651-2509. E-mail: zeichen{at}gsu.edu.

Editor: J. N. Weiser

{dagger} C.S.B. and C.T. contributed equally to this work.

Infection and Immunity, September 2005, p. 5743-5753, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5743-5753.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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