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Infection and Immunity, May 2008, p. 2189-2201, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01609-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Limited Role for Iron Regulation in Coxiella burnetii Pathogenesis ^,

Heather L. Briggs,¹ Nicolein Pul,¹ Rekha Seshadri,² Mary J. Wilson,¹ Claudia Tersteeg,¹ Kasi E. Russell-Lodrigue,¹ Masako Andoh,¹ Andreas J. Bäumler,³ and James E. Samuel^1*

TAMUS Health Science Center, Department of Microbial and Molecular Pathogenesis, College Station, Texas,¹ The Institute of Genomic Research, Rockville, Maryland,² University of California, Department of Medical Microbiology and Immunology, Davis, California³

Received 5 December 2007/ Returned for modification 9 January 2008/ Accepted 20 February 2008

In gram-negative bacteria, iron acquisition proteins are commonly regulated by Fur (ferric uptake regulator), which binds iron-regulated promoters (the Fur box). We hypothesized that Coxiella burnetii requires iron and employs an iron-regulatory system and used various approaches to define a Fur regulon. Cloned C. burnetii fur complemented an Escherichia coli fur deletion mutant. A ferrous iron transporter gene (CBU1766), a putative iron binding protein-encoding gene (CBU0970), and a cation efflux pump gene (CBU1362) were identified by genome annotation and using a Fur titration assay. Bioinformatically predicted Fur box-containing promoters were tested for transcriptional control by iron. Five genes demonstrated at least a twofold induction with minimal iron. Putatively regulated genes were evaluated in a two-plasmid regulator/promoter heterologous expression system. These data suggested a very limited Fur-regulated system in C. burnetii. In an in vitro tissue culture model, a significant increase in bacterial growth was observed with infected cells treated with deferoxamine in comparison to growth under iron-replete conditions. In an iron-overloaded animal model in vivo, the level of bacterial growth detected in the iron-injected animals was significantly decreased in comparison to growth in control animals. In a low-iron-diet animal model, a significant increase in splenomegaly was observed, but no significant change in bacterial growth was identified. The small number of predicted iron acquisition systems, few Fur-regulated genes, and enhanced replication under a decreased iron level predict a requirement of a low level of iron for survival, perhaps to avoid creation of additional reactive oxygen radicals.

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* Corresponding author. Mailing address: Department of Microbial and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, TX 77843-1114. Phone: (979) 862-1684. Fax: (979) 845-3479. E-mail: jsamuel{at}tamhsc.edu

Published ahead of print on 3 March 2008.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: R. P. Morrison

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Infection and Immunity, May 2008, p. 2189-2201, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01609-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.