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Infect. Immun. doi:10.1128/IAI.01250-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of MglA-regulated genes reveals novel virulence factors in F. tularensis

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143. Biosciences Directorate, Lawrence Livermore National Laboratory, California 94550, USA

^* To whom correspondence should be addressed. Email: dmonack{at}stanford.edu.

	Abstract

The facultative intracellular bacterium Francisella tularensis causes the zoonotic disease tularemia. F. tularensis resides within host macrophages in vivo and this ability is essential for pathogenesis. The transcription factor MglA is required for expression of several Francisella genes that are necessary for replication in macrophages and for virulence in mice. We hypothesized that identification of MglA-regulated genes in the Francisella genome by transcriptional profiling of wild-type and mglA mutant bacteria would lead to the discovery of new virulence factors utilized by F. tularensis. One hundred and two MglA-regulated genes were identified, the majority of which were positively regulated, including all of the Francisella Pathogenicity Island (FPI) genes. We mutated novel MglA-regulated genes and tested the mutants for their ability to replicate and to induce cytotoxicity in macrophages, and to grow in mice. Mutants in MglA-regulated genes within the FPI (pdpB and cds2), as well as outside the FPI (FTT0989, oppB, and FTT1209c), were either attenuated or hypervirulent in macrophages as compared to the wild-type strain. All of these mutants exhibited decreased fitness in vivo in competition experiments with wild-type bacteria. We have identified 5 new Francisella virulence genes and our results suggest that characterization of additional MglA-regulated genes will yield further insights into the pathogenesis of this bacterium.

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