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Journal of Bacteriology, November 2009, p. 6855-6864, Vol. 191, No. 22
0021-9193/09/$08.00+0     doi:10.1128/JB.00995-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Global Transcriptional Response to Spermine, a Component of the Intramacrophage Environment, Reveals Regulation of Francisella Gene Expression through Insertion Sequence Elements{triangledown} ,{dagger}

Paul E. Carlson Jr.,1,{ddagger} Joseph Horzempa,1,{ddagger} Dawn M. O'Dee,1,{ddagger} Cory M. Robinson,1 Panayiotis Neophytou,2 Alexandros Labrinidis,2 and Gerard J. Nau1,3,4*

Department of Microbiology and Molecular Genetics,1 Department of Computer Science,2 Department of Medicine, Division of Infectious Diseases,3 Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 152614

Received 27 July 2009/ Accepted 31 August 2009

Tularemia is caused by the category A biodefense agent Francisella tularensis. This bacterium is associated with diverse environments and a plethora of arthropod and mammalian hosts. How F. tularensis adapts to these different conditions, particularly the eukaryotic intracellular environment in which it replicates, is poorly understood. Here, we demonstrate that the polyamines spermine and spermidine are environmental signals that alter bacterial stimulation of host cells. Genomewide analysis showed that F. tularensis LVS undergoes considerable changes in gene expression in response to spermine. Unexpectedly, analysis of gene expression showed that multiple members of two classes of Francisella insertion sequence (IS) elements, ISFtu1 and ISFtu2, and the genes adjacent to these elements were induced by spermine. Spermine was sufficient to activate transcription of these IS elements and of nearby genes in broth culture and in macrophages. Importantly, the virulent strain of F. tularensis, Schu S4, exhibited similar phenotypes of cytokine induction and gene regulation in response to spermine. Distinctions in gene expression changes between Schu S4 and LVS at one orthologous locus, however, correlated with differences in IS element location. Our results indicate that spermine and spermidine are novel triggers to alert F. tularensis of its eukaryotic host environment. The results reported here also identify an unexpected mechanism of gene regulation controlled by a spermine-responsive promoter contained within IS elements. Different arrangements of these mobile genetic elements among Francisella strains may contribute to virulence by conveying new expression patterns for genes from different strains.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Phone: (412) 383-9986. Fax: (412) 624-1401. E-mail: gjnau{at}pitt.edu

{triangledown} Published ahead of print on 11 September 2009.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

{ddagger} These authors contributed equally to this work.

Journal of Bacteriology, November 2009, p. 6855-6864, Vol. 191, No. 22
0021-9193/09/$08.00+0     doi:10.1128/JB.00995-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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