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Infection and Immunity, August 2008, p. 3690-3699, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00262-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Combined Deletion of Four Francisella novicida Acid Phosphatases Attenuates Virulence and Macrophage Vacuolar Escape{triangledown} ,{dagger}

Nrusingh P. Mohapatra,1 Shilpa Soni,1 Thomas J. Reilly,2 Jirong Liu,3 Karl E. Klose,3 and John S. Gunn1*

Center for Microbial Interface Biology, Department of Molecular Virology, Immunology and Medical Genetics, and Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University, Columbus, Ohio 43210,1 Department of Veterinary Pathobiology and Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, Missouri 65211,2 Department of Biology, University of Texas at San Antonio, South Texas Center for Emerging Infectious Diseases, San Antonio, Texas 782493

Received 25 February 2008/ Returned for modification 28 March 2008/ Accepted 2 May 2008

Francisella tularensis is a facultative intracellular pathogen and the etiologic agent of tularemia. It is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. Bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. The goal of this study was to delete the four primary acid phosphatases (Acps) from Francisella novicida and examine the interactions of mutant strains with macrophages, as well as the virulence of these strains in mice. We constructed F. novicida mutants with various combinations of acp deletions and showed that loss of the four Acps (AcpA, AcpB, AcpC, and histidine acid phosphatase [Hap]) in an F. novicida strain ({Delta}ABCH) resulted in a 90% reduction in acid phosphatase activity. The {Delta}ABCH mutant was defective for survival/growth within human and murine macrophage cell lines and was unable to escape from phagosome vacuoles. With accumulation of Acp deletions, a progressive loss of virulence in the mouse model was observed. The {Delta}ABCH strain was dramatically attenuated and was an effective single-dose vaccine against homologous challenge. Furthermore, both acpA and hap were induced when the bacteria were within host macrophages. Thus, the Francisella acid phosphatases cumulatively play an important role in intracellular trafficking and virulence.

* Corresponding author. Mailing address: The Ohio State University, Biomedical Research Tower, Rm. 1006, 460 W. 12th Ave., Columbus, OH 43210-1214. Phone: (614) 292-6036. Fax: (614) 292-5495. E-mail: gunn.43{at}osu.edu

{triangledown} Published ahead of print on 19 May 2008.

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

Editor: V. J. DiRita

Infection and Immunity, August 2008, p. 3690-3699, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00262-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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