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Infection and Immunity, March 2004, p. 1333-1340, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1333-1340.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of Novel Virulence-Associated Genes via Genome Analysis of Hypothetical Genes

Sara Garbom,¹ Åke Forsberg,^1,2 Hans Wolf-Watz,¹ and Britt-Marie Kihlberg^2*

Department of Molecular Biology, Umeå University, S-901 87 Umeå,¹ Department of Medical Countermeasures, Division of NBC Defence, Swedish Defence Research Agency, S-901 82 Umeå, Sweden²

Received 20 May 2003/ Returned for modification 11 August 2003/ Accepted 13 November 2003

The sequencing of bacterial genomes has opened new perspectives for identification of targets for treatment of infectious diseases. We have identified a set of novel virulence-associated genes (vag genes) by comparing the genome sequences of six human pathogens that are known to cause persistent or chronic infections in humans: Yersinia pestis, Neisseria gonorrhoeae, Helicobacter pylori, Borrelia burgdorferi, Streptococcus pneumoniae, and Treponema pallidum. This comparison was limited to genes annotated as hypothetical in the T. pallidum genome project. Seventeen genes with unknown functions were found to be conserved among these pathogens. Insertional inactivation of 14 of these genes generated nine mutants that were attenuated for virulence in a mouse infection model. Out of these nine genes, five were found to be specifically associated with virulence in mice as demonstrated by infection with Yersinia pseudotuberculosis in-frame deletion mutants. In addition, these five vag genes were essential only in vivo, since all the mutants were able to grow in vitro. These genes are broadly conserved among bacteria. Therefore, we propose that the corresponding vag gene products may constitute novel targets for antimicrobial therapy and that some vag mutants could serve as carrier strains for live vaccines.

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* Corresponding author. Present address: Department of Molecular Sciences, AstraZeneca R & D Mölndal, S-43183 Mölndal, Sweden. Phone: 46-31-706-5889. Fax: 46-31-776-3872. E-mail: Britt-Marie.Kihlberg{at}astrazeneca.com.

Editor: B. B. Finlay

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Infection and Immunity, March 2004, p. 1333-1340, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1333-1340.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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