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Infection and Immunity, August 2008, p. 3664-3671, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00374-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Native Outer Membrane Proteins Protect Mice against Pulmonary Challenge with Virulent Type A Francisella tularensis

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,¹ Department of Microbiology, Roy J. and Lucille A. Carver School of Medicine, University of Iowa, Iowa City, Iowa 52242²

Received 24 March 2008/ Returned for modification 30 April 2008/ Accepted 21 May 2008

Francisella tularensis is a gram-negative intracellular bacterium and the causative agent of the zoonotic disease tularemia. F. tularensis is a category A select agent and thus a potential agent of bioterrorism. Whereas an F. tularensis live, attenuated vaccine strain (LVS) is the basis of an investigational vaccine, this vaccine is not licensed for human use because of efficacy and safety concerns. In the present study, we immunized mice with isolated native outer membrane proteins (OMPs), ethanol-inactivated LVS (iLVS), or purified LVS lipopolysaccharide (LPS) and assessed the ability of each vaccine preparation to protect mice against pulmonary challenge with the virulent type A F. tularensis strain SchuS4. Antibody isotyping indicated that both Th1 and Th2 antibody responses were generated in mice after immunization with OMPs or iLVS, whereas LPS immunization resulted in only immunoglobulin A production. In survival studies, OMP immunization provided the greatest level of protection (50% survival at 20 days after infection with SchuS4), and there were associated 3-log reductions in the spleen and liver bacterial burdens (compared to nonvaccinated mice). Cytokine quantitation for the sera of SchuS4-challenged mice indicated that OMP and iLVS immunizations induced high levels of tumor necrosis factor alpha and interleukin-2 (IL-2) production, whereas only OMP immunization induced high levels of IL-10 production. By comparison, high levels of proinflammatory cytokines, including RANTES, granulocyte colony-stimulating factor, IL-6, IL-1, IL-12p40, and KC, in nonvaccinated mice indicated that these cytokines may facilitate disease progression. Taken together, the results of this study demonstrate the potential utility of an OMP subunit (acellular) vaccine for protecting mammals against type A F. tularensis.

Published ahead of print on 27 May 2008.

Editor: J. B. Bliska