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Infection and Immunity, May 2003, p. 2584-2590, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2584-2590.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Characterization of the Role of the Divalent Metal Ion-Dependent Transcriptional Repressor MntR in the Virulence of Staphylococcus aureus

Masaru Ando,1,{dagger} Yukari C. Manabe,1,2 Paul J. Converse,2 Eishi Miyazaki,1,{dagger} Robert Harrison,3 John R. Murphy,4 and William R. Bishai1,2*

Division of Disease Control, Department of International Health, Johns Hopkins University Bloomberg School of Public Health,1 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,2 Section of Molecular Medicine, Department of Medicine, Boston University School of Medicine, Boston,4 Advanced Microbial Solutions, Milford, Massachusetts3

Received 11 December 2002/ Returned for modification 11 January 2003/ Accepted 14 February 2003

DtxR-type metal ion-dependent repressors, present in many bacterial pathogens, may regulate expression of virulence genes such as that encoding diphtheria toxin. SirR, a DtxR homologue initially identified in Staphylococcus epidermidis, governs the expression of the adjacent sitABC operon encoding a putative metal ion ABC transporter system. We identified a sirR homologue, mntR, in Staphylococcus aureus and demonstrated by gel shift assay that the corynebacterial repressor DtxR binds to the S. aureus mntABC operator in the presence of Fe2+ or Mn2+. Since a mutant DtxR, DtxR(E175K), functions as an iron-independent hyperrepressor in certain settings, we constructed a heterodiploid S. aureus strain expressing dtxR(E175K) from the native mntR promoter. Transcription of the S. aureus mntABC operon was repressed in the presence of Fe2+ or Mn2+ in wild-type and heterodiploid S. aureus strains. Under metal ion-limiting conditions, mntABC transcription was reduced but not abolished in S. aureus isolates expressing dtxR(E175K) compared with an isogenic control, suggesting that DtxR(E175K) binds the S. aureus MntR box in vivo. Under all conditions tested, mntABC transcription in the dtxR(E175K)-expressing strain was reduced relative to the isogenic control, indicating that DtxR(E175K) function was constitutively active. In the mouse skin abscess model, dtxR(E175K)-expressing S. aureus recombinants showed significantly reduced CFU levels compared with the isogenic wild-type control. We conclude that the S. aureus MntR box is recognized by corynebacterial DtxR proteins and thus belongs to the DtxR family of metal-dependent operator sites. Moreover, constitutive repression by DtxR(E175K) reduces the virulence of S. aureus in the mouse skin abscess model.

* Corresponding author. Mailing address: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 424 North Bond St., Rm 112, Baltimore, MD 21205. Phone: (410) 955-3507. Fax: (410) 614-8173. E-mail: wbishai{at}jhsph.edu.

Editor: W. A. Petri, Jr.

{dagger} Present address: Division of Pulmonary Diseases, Department of Immunology and Allergy, Oita Medical University, Oita, Japan.

Infection and Immunity, May 2003, p. 2584-2590, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2584-2590.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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