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Infect. Immun. doi:10.1128/IAI.01789-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A defined O-antigen polysaccharide mutant of Francisella tularensis LVS has attenuated virulence while retaining its protective capacity

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA; National Research Council Canada, Institute for Biological Sciences, Ottawa, Ont., Canada KIA OR6

^* To whom correspondence should be addressed. Email: dennis_kasper{at}hms.harvard.edu.

	Abstract

Francisella tularensis, the causative agent of tularemia, has been designated a CDC category A select agent because of its low infective dose (< 10 colony-forming units), its ready transmission by aerosol, and its ability to produce severe morbidity and high mortality. The identification and characterization of this organism's virulence determinants will facilitate the development of a safe and effective vaccine. We report that inactivation of the wbtA-encoded dehydratase of the O-antigen polysaccharide (O-PS) locus of the still-unlicensed live vaccine strain of F. tularensis (LVS) results in a mutant (Ft.LVS::wbtA) with remarkably attenuated virulence. Western blot analysis and immune electron microscopy studies associate this loss of virulence with a complete lack of surface O-PS expression. A likely mechanism for attenuation is shown to be the transformation from serum resistance in the wild-type strain to serum sensitivity in the mutant. Despite this significant attenuation in virulence, the Ft.LVS::wbtA mutant remains immunogenic and confers protective immunity to mice against challenge with an otherwise-lethal dose of either F. tularensis LVS or a fully virulent clinical isolate of F. tularensis type B. Recognition and characterization of the pivotal role of O-PS in the virulence of this intracellular bacterial pathogen may have broad implications for the creation of a safe and efficacious vaccine.

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