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Infection and Immunity, December 2005, p. 8069-8078, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8069-8078.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Virulence and Karyotype Analyses of rad52 Mutants of Candida albicans: Regeneration of a Truncated Chromosome of a Reintegrant Strain (rad52/RAD52) in the Host

Georgetown University Medical Center, Department of Microbiology & Immunology, Washington, D.C.,¹ Department of Microbiology, Universdad de Extremadura, Badajoz, Spain,² Department of Immunology, Microbiology & Parasitology, Universidad del Pais Vasco, Leioia, Vizcaya, Spain³

Received 21 July 2005/ Returned for modification 24 August 2005/ Accepted 7 September 2005

The virulence of Candida albicans mutants lacking one or both copies of RAD52, a gene involved in homologous recombination (HR), was evaluated in a murine model of hematogenously disseminated candidiasis. In this study, the virulence of the rad52 mutant was dependent upon the inoculum concentration. Mice survived at a cell inoculum of 1 x 10⁶, but there was a decrease in survival time at dosages of 1.5 x 10⁶ and especially at 3 x 10⁶ cells per animal. The heterozygote RAD52/rad52 behaved like wild type, whereas a reintegrant strain was intermediate in its ability to cause death compared to these strains and to the avirulent rad52/rad52 null at inocula of 1 x 10⁶ and 1.5 x 10⁶ cells. A double mutant, lig4/lig4/rad52/rad52, was avirulent at all inocula used. PCR analysis of the RAD52 and/or LIG4 loci showed that all strains recovered from animals matched the genotype of the inoculated strains. Analysis of the electrophoretical karyotypes indicated that the inoculated, reintegrant strain carried a large deletion in one copy of chromosome 6 (the shortest homologue, or Chr6b). Interestingly, truncated Chr6b was regenerated in all the strains recovered from moribund animals using the homologue as a template. Further, regeneration of Chr6b was paralleled by an increase in virulence that was still lower than that of wild type, likely because of the persistent loss of heterozygosity in the regenerated region. Overall, our results indicate that systemic candidiasis can develop in the absence of HR, but simultaneous elimination of both recombination pathways, HR and nonhomologous end-joining, suppresses virulence even at very high inocula.

Editor: T. R. Kozel

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