Virulence of a phosphoribosylaminoimidazole carboxylase-deficient Candida albicans strain in an immunosuppressed murine model of systemic candidiasis.
The relative pathogenicities of three Candida albicans strains differing in the function of ADE2 (the gene encoding phosphoribosylaminoimidazole carboxylase) were evaluated in a murine candidiasis model. C. albicans strain CAI7 (ade2/ade2), previously constructed by site-specific recombination, was avirulent in immunosuppressed mice compared to the parent strain, CAF2-1, and a heterozygous ADE2/ade2 strain obtained by transforming CAI7 with a wild-type allele. The reduced virulence of CAI7 was correlated with the inability to proliferate in either synthetic medium or serum without the exogenous addition of >10 microg of adenine/ml. The loss of virulence upon site-specific disruption of the ade2 locus, and the restoration of wild-type virulence with the repair of just one ade2 allele, confirmed that the ADE2 gene and de novo purine biosynthesis were required for Candida pathogenicity. The potential of the phosphoribosylaminoimidazole carboxylase enzyme as a novel target for antifungal drug discovery is discussed.
Searle Research and Development, Pharmacia Company, St. Louis, Missouri 63198, USA.
M
M
Donovan
J J
JJ
Schumuke
W A
WA
Fonzi
S L
SL
Bonar
K
K
Gheesling-Mullis
G S
GS
Jacob
V J
VJ
Davisson
S B
SB
Dotson
D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000254:growth & development / Q000472:pathogenicity; D002177:Candidiasis / Q000209:etiology* / Q000276:immunology; D002262:Carboxy-Lyases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D007165:Immunosuppression Therapy; D051379:Mice; D014774:Virulence
D002262:Carboxy-Lyases; C022378:phosphoribosylaminoimidazole carboxylase