Reduced virulence of HWP1-deficient mutants of Candida albicans and their interactions with host cells

The Candida albicans gene HWP1 encodes a surface protein that is required f or normal hyphal development in vitro. We used mutants lacking one or both alleles of HWP1 to investigate the role of this gene in virulence. Mice inf ected intravenously,vith the homozygous hwp1 null mutant, CAL3, survived a median of >14 days, whereas mice infected with a control strain containing two functional alleles of HWP1 survived only 3.5 days. After 1 day of infec tion, all strains produced similar levels of infection in the kidneys, sple en, and blood, However, after 2 and 3 days, there was a significant decreas e in the number of organisms in the kidneys of the mice infected with CAL3. This finding suggests that the hwp1 homozygous null mutant is normal in it s ability to initiate infection but deficient in its capacity to maintain i nfection. CAL3 also germinated minimally in the kidneys. The ability of the heterozygous null mutant to germinate and cause mortality in mice was inte rmediate to CAL3, suggesting a gene dosage effect. To investigate potential mechanisms for the diminished virulence of CAL3, we examined its interacti ons with endothelial cells and neutrophils in vitro. CAL3 caused less endot helial cell injury than the heterozygous hwp1 mutant. We conclude that the HWP1 gene product is important for both in vivo hyphal development and path ogenicity of C. albicans. Also, the ability to form filaments may be critic al for candidal virulence by enabling the fungus to induce cellular injury and maintain a deep-seated infection.