Candida albicans RIM101 pH response pathway is required for host-pathogen interactions

Abstract

The ability of Candida albicans to respond to diverse environments is critical for its success as a pathogen. The RIM101 pathway controls gene expression and the yeast-to-hyphal transition in C. albicans in response to changes in environmental pH in vitro. In this study, we found that the RIM101 pathway is necessary in vivo for pathogenesis. First, we show that rim101(-)/rim101(-) and rim8(-)/rim8(-) mutants have a significant reduction in virulence using the mouse model of hematogenously disseminated systemic candidiasis. Second, these mutants show a marked reduction in kidney pathology. Third, the rim101(-)/rim101(-) and rim8(-)/rim8(-) mutants show defects in the ability to damage endothelial cells in situ. Finally, we show that an activated allele of RIM101, RIM101-405, is a suppressor of the rim8(-) mutation in vivo as it rescues the virulence, histological, and endothelial damage defects of the rim8(-)/rim8(-) mutant. These results demonstrate that the RIM101 pathway is required for C. albicans virulence in vivo and that the function of Rim8p in pathogenesis is to activate Rim101p.

FIG. 1

Survival curves of mice following injection with C. albicans. Experiments were done simultaneously but broken up to simplify viewing. Survival was monitored in mice infected with RIM101 mutants (A), RIM8 mutants (B), and RIM8 suppressor strains (C). No mice died between the last time point (day 10) and the end of the experiment (day 14).

FIG. 2

Histological samples of kidneys infected with C. albicans for 40 h. Mice were injected with the wild-type (A and B), rim101⁻/rim101⁻ (C and D), rim101⁻/rim101⁻ +RM101 (E and F), rim8⁻/rim8⁻ (G and H), and rim8⁻/rim8⁻ +RIM101-405 (I and J) strains. Sections were visualized using either a 10× (A, C, E, G, and I) or a 40× (B, D, F, H, and J) objective. Arrows denote microabscesses in the 10× panels and representative C. albicans cells in the 40× panels. Note that arrows are absent in panels C and D due to the absence of visible microabscesses and C. albicans cells, respectively.

FIG. 3

Endothelial damage. Damage to endothelial cells was determined by a chromium release assay. Wild-type and RIM101 pathway mutants were incubated with endothelial cells for 3 h, and release of ⁵¹Cr from lysed endothelial cells was measured. Asterisks indicate values that statistically significantly differ from wild-type values (P < 0.001) by analysis of variance.