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Journal of Clinical Microbiology, July 2003, p. 2924-2931, Vol. 41, No. 7
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.7.2924-2931.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Genome-Wide DNA Microarray Analysis of Francisella tularensis Strains Demonstrates Extensive Genetic Conservation within the Species but Identifies Regions That Are Unique to the Highly Virulent F. tularensis subsp. tularensis

Martien Broekhuijsen,1 Pär Larsson,2 Anders Johansson,2,3,4 Mona Byström,2 Ulla Eriksson,2 Eva Larsson,2 Richard G. Prior,5 Anders Sjöstedt,3 Richard W. Titball,5,6 and Mats Forsman2*

TNO Prins Maurits Laboratory, Rijswijk, The Netherlands,1 Swedish Defence Research Agency,2 Department of Clinical Microbiology, Bacteriology,3 Department of Clinical Microbiology, Infectious Diseases, Umeå University, Umeå, Sweden,4 Defence Science and Technology Laboratory, CBS Porton Down, Salisbury,5 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom6

Received 19 August 2002/ Returned for modification 30 October 2002/ Accepted 26 March 2003

Francisella tularensis is a potent pathogen and a possible bioterrorism agent. Little is known, however, to explain the molecular basis for its virulence and the distinct differences in virulence found between the four recognized subspecies, F. tularensis subsp. tularensis, F. tularensis subsp. mediasiatica, F. tularensis subsp. holarctica, and F. tularensis subsp. novicida. We developed a DNA microarray based on 1,832 clones from a shotgun library used for sequencing of the highly virulent strain F. tularensis subsp. tularensis Schu S4. This allowed a genome-wide analysis of 27 strains representing all four subspecies. Overall, the microarray analysis confirmed a limited genetic variation within the species F. tularensis, and when the strains were compared, at most 3.7% of the probes showed differential hybridization. Cluster analysis of the hybridization data revealed that the causative agents of type A and type B tularemia, i.e., F. tularensis subsp. tularensis and F. tularensis subsp. holarctica, respectively, formed distinct clusters. Despite marked differences in their virulence and geographical origin, a high degree of genomic similarity between strains of F. tularensis subsp. tularensis and F. tularensis subsp. mediasiatica was apparent. Strains from Japan clustered separately, as did strains of F. tularensis subsp. novicida. Eight regions of difference (RD) 0.6 to 11.5 kb in size, altogether comprising 21 open reading frames, were identified that distinguished strains of the moderately virulent subspecies F. tularensis subsp. holarctica and the highly virulent subspecies F. tularensis subsp. tularensis. One of these regions, RD1, allowed for the first time the development of an F. tularensis-specific PCR assay that discriminates each of the four subspecies.

* Corresponding author. Mailing address: Swedish Defense Research Agency, SE 901 82, Umeå, Sweden. Phone: 46 90 106669. Fax: 46 90 106800. E-mail: mats.forsman{at}foi.se.

Journal of Clinical Microbiology, July 2003, p. 2924-2931, Vol. 41, No. 7
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.7.2924-2931.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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