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Infection and Immunity, December 2005, p. 8345-8352, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8345-8352.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Mutant of Francisella tularensis Strain SCHU S4 Lacking the Ability To Express a 58-Kilodalton Protein Is Attenuated for Virulence and Is an Effective Live Vaccine

Susan Twine,1 Mona Byström,2 Wangxue Chen,1 Mats Forsman,2 Igor Golovliov,3 Anders Johansson,2,4 John Kelly,1 Helena Lindgren,3 Kerstin Svensson,2 Carl Zingmark,3 Wayne Conlan,1 and Anders Sjöstedt3*

National Research Council Canada, Institute for Biological Sciences, Ottawa, Canada,1 Swedish Defence Research Agency, SE-90182 Umeå, Sweden,2 Department of Clinical Microbiology and Clinical Bacteriology,3 Department of Infectious Diseases, Umeå University, SE-90185 Umeå, Sweden4

Received 2 August 2005/ Returned for modification 31 August 2005/ Accepted 7 September 2005

Francisella tularensis subsp. tularensis (type A) strain SCHU S4 is a prototypic strain of the pathogen that is highly virulent for humans and other mammals. Its intradermal (i.d.) 50% lethal dose (LD50) for mice is <10 CFU. We discovered a spontaneous mutant, designated FSC043, of SCHU S4 with an i.d. LD50 of >108 CFU. FSC043 effectively vaccinated mice against challenge with a highly virulent type A strain, and the protective efficacy was at least as good as that of F. tularensis LVS, an empirically attenuated strain which has been used as an efficacious human vaccine. Comparative proteomics was used to identify two proteins of unknown function that were identified as defective in LVS and FSC043, and deletion mutants of SCHU S4 were created for each of the two encoding genes. One mutant, the {Delta}FTT0918 strain, failed to express a 58-kDa protein, had an i.d. LD50 of ~105 CFU, and was found to be less capable than SCHU S4 of growing in peritoneal mouse macrophages. Mice that recovered from sublethal infection with the {Delta}FTT0918 mutant survived when challenged 2 months later with >100 LD50s of the highly virulent type A strain FSC033. This is the first report of the generation of defined mutants of F. tularensis subsp. tularensis and their use as live vaccines.

* Corresponding author. Mailing address: Department of Clinical Microbiology, Clinical Bacteriology, Umeå University, SE-901 85 Umeå, Sweden. Fax: 46 90 785 2225. Phone: 46 90 785 1120. E-mail: anders.sjostedt{at}climi.umu.se.

Editor: D. L. Burns

Infection and Immunity, December 2005, p. 8345-8352, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8345-8352.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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