Effects of Deleting the C. albicans Gene INT1 on Mortality and Yeast Tissue Survival in a Mouse Model of Fungemia † 811

Virulence among Candida species correlates with adhesion. The C. albicans gene INT1 encodes a surface borne adhesin(Int1p). When both copies of INT1 are disrupted in C. albicans, or with reintegration of a single copy of INT1 into its native chromosomal locus, in vitro adhesion to human epithelial cells (HeLa) and the formation of hyphal elements are both diminished. We sought to evaluate the virulence and tissue invasion of these mutant yeasts in a mouse model of fungemia.

Mice were injected IV with 2×10⁵C. albicans CAF2(parent strain, INT1/INT1),or C. albicans CAG3 (homozygous deletion, int1/int1),or C. albicans CAG5 (heterozygous reintegrant, int1/int1+INT1*)[n=50 for each group]. Mortality was monitored and mice were sacrificed on days 1, 7, 14 and 21 with analysis of kidney tissue for viable candida (reported as CFU yeast log₁₀/g tissue, n=6-8 per group per time point). 40% of mice injected with the parent CAF2 and 36% of mice injected with CAG5 died, compared to 22% of mice injected with CAG3 (p<0.05, Chi-square). Thus, C. albicans virulence correlates with the presence of INT1.

As shown in the table below, analysis of kidney tissue showed no significant differences in the recovery of viable yeasts on days 1 and 7. However, by day 14 the concentrations of CAG3 found in the kidneys were significantly greater than that seen with either the parent CAF2 or the reintegrant CAG5 (*p<0.04, ANOVA followed by Fisher's PLSD). By day 21 there were no yeast detected in the kidneys of mice injected with the parent CAF2 (2.1 log₁₀=lower limit of assay detection), while the concentration of CAG3 remained significantly higher than CAF2 (**p<0.01) and the concentration of CAG5 was intermediate (NS compared to either CAF2 or CAG3). Therefore, deletion of both copies of INT1 resulted in fewer mouse deaths, but prolonged tissue survival. These results suggest a previously unsuspected interaction between the expression of INT1 and murine immune mechanisms that facilitate clearance of the yeast in animals surviving the initial infection.

Table 1 No caption available.