Affiliation:
1. Georgetown
University Medical Center, Department of Microbiology & Immunology,
Washington, D.C.
2. Department of Microbiology,
Universdad de Extremadura, Badajoz, Spain
3. Department of
Immunology, Microbiology & Parasitology, Universidad del
Pais Vasco, Leioia, Vizcaya,
Spain
Abstract
ABSTRACT
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
Δ mutant was dependent upon the inoculum
concentration. Mice survived at a cell inoculum of 1 ×
10
6
, but there was a decrease in survival time at dosages of
1.5 × 10
6
and especially at 3 ×
10
6
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 ×
10
6
and 1.5 × 10
6
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Cited by
27 articles.
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