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Infection and Immunity, May 2009, p. 1866-1880, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01496-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hfq, a Novel Pleiotropic Regulator of Virulence-Associated Genes in Francisella tularensis{triangledown}

Karin L. Meibom,1,2 Anna-Lena Forslund,3,4 Kerstin Kuoppa,3 Khaled Alkhuder,1,2 Iharilalao Dubail,1,2 Marion Dupuis,1,2 Åke Forsberg,3,4 and Alain Charbit1,2*

Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades, Paris F-75015, France,1 INSERM, U570, Unit of Pathogenesis of Systemic Infections, Paris F-75015, France,2 FOI Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden,3 Laboratory for Molecular Infection Medicine Sweden and Umeå Centre for Microbial Research, Department of Molecular Biology Umeå University, SE-901 87 Umeå, Sweden4

Received 9 December 2008/ Accepted 6 February 2009

Francisella tularensis is a highly infectious pathogen that infects animals and humans, causing tularemia. The ability to replicate within macrophages is central for virulence and relies on expression of genes located in the Francisella pathogenicity island (FPI), as well as expression of other genes. Regulation of FPI-encoded virulence gene expression in F. tularensis involves at least four regulatory proteins and is not fully understood. Here we studied the RNA-binding protein Hfq in F. tularensis and particularly the role that it plays as a global regulator of gene expression in stress tolerance and pathogenesis. We demonstrate that Hfq promotes resistance to several cellular stresses (including osmotic and membrane stresses). Furthermore, we show that Hfq is important for the ability of the F. tularensis vaccine strain LVS to induce disease and persist in organs of infected mice. We also demonstrate that Hfq is important for stress tolerance and full virulence in a virulent clinical isolate of F. tularensis, FSC200. Finally, microarray analyses revealed that Hfq regulates expression of numerous genes, including genes located in the FPI. Strikingly, Hfq negatively regulates only one of two divergently expressed putative operons in the FPI, in contrast to the other known regulators, which regulate the entire FPI. Hfq thus appears to be a new pleiotropic regulator of virulence in F. tularensis, acting mostly as a repressor, in contrast to the other regulators identified so far. Moreover, the results obtained suggest a novel regulatory mechanism for a subset of FPI genes.

* Corresponding author. Mailing address: Faculté de Médecine Necker, 156, rue de Vaugirard, 75730 Paris Cedex 15, France. Phone: 33 1-40 61 53 76. Fax: 33 1-40 61 55 92. E-mail: alain.charbit{at}inserm.fr

{triangledown} Published ahead of print on 17 February 2009.

Editor: W. A. Petri, Jr.

Infection and Immunity, May 2009, p. 1866-1880, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01496-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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