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Infection and Immunity, May 2007, p. 2421-2431, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01821-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The ChrA-ChrS and HrrA-HrrS Signal Transduction Systems Are Required for Activation of the hmuO Promoter and Repression of the hemA Promoter in Corynebacterium diphtheriae{triangledown}

Lori A. Bibb, Carey A. Kunkle, and Michael P. Schmitt*

Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Received 16 November 2006/ Returned for modification 8 February 2007/ Accepted 28 February 2007

Transcription of the Corynebacterium diphtheriae hmuO gene, which encodes a heme oxygenase involved in heme iron utilization, is activated in a heme- or hemoglobin-dependent manner in part by the two-component system ChrA-ChrS. Mutation of either the chrA or the chrS gene resulted in a marked reduction of hemoglobin-dependent activation at the hmuO promoter in C. diphtheriae; however, it was observed that significant levels of hemoglobin-dependent expression were maintained in the mutants, suggesting that an additional activator is involved in regulation. A BLAST search of the C. diphtheriae genome sequence revealed a second two-component system, encoded by DIP2268 and DIP2267, that shares similarity with ChrS and ChrA, respectively; we have designated these genes hrrS (DIP2268) and hrrA (DIP2267). Analysis of hmuO promoter expression demonstrated that hemoglobin-dependent activity was fully abolished in strains from which both the chrA-chrS and the hrrA-hrrS two-component systems were deleted. Similarly, deletion of the sensor kinase genes chrS and hrrS or the genes encoding both of the response regulators chrA and hrrA also eliminated hemoglobin-dependent activation at the hmuO promoter. We also show that the regulators ChrA-ChrS and HrrA-HrrS are involved in the hemoglobin-dependent repression of the promoter upstream of hemA, which encodes a heme biosynthesis enzyme. Evidence for cross talk between the ChrA-ChrS and HrrA-HrrS systems is presented. In conclusion, these findings demonstrate that the ChrA-ChrS and HrrA-HrrS regulatory systems are critical for full hemoglobin-dependent activation at the hmuO promoter and also suggest that these two-component systems are involved in the complex mechanism of the regulation of heme homeostasis in C. diphtheriae.

* Corresponding author. Mailing address: DBPAP, CBER, FDA, Bldg. 29, Room 108, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 435-2424. Fax: (301) 402-2776. E-mail: michael.schmitt{at}fda.hhs.gov

{triangledown} Published ahead of print on 12 March 2007.

Editor: V. J. DiRita

Infection and Immunity, May 2007, p. 2421-2431, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01821-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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