VIRULENCE AND HYPHAL FORMATION OF CANDIDA-ALBICANS REQUIRE THE STE20P-LIKE PROTEIN-KINASE CACLA4P

Background: The pathogenic fungus Candida albicans is capable of a mor phological transition from a unicellular budding yeast to a filamentou s form. Extensive filamentous growth leads to the formation of mycelia displaying hyphae with branches and lateral buds, Hyphae have been ob served to adhere to and invade host tissues more readily than the yeas t form, suggesting that filamentous growth may contribute to the virul ence of this major human pathogen, A molecular and genetic understandi ng of the potential role of morphological switching in the pathogenici ty of C. albicans would be of significant benefit in view of the incre asing incidence of candidiasis. Results: The CaCLA4 gene of C. albican s was cloned by functional complementation of the growth defect of cel ls of the budding yeast Saccharomyces cerevisiae deleted for the STE20 gene and the CLA4 gene. CaCLA4 encodes a member of the Ste20p family of serine/threonine protein kinases and is characterized by a pleckstr in homology domain and a Cdc42p-binding domain in its amino-terminal n on-catalytic region, Deletion of both alleles of CaCLA4 in C. albicans caused defects in hyphal formation in vitro, in both synthetic liquid and solid media, and in vivo in a mouse model for systemic candidiasi s. The gene deletions reduced colonization of the kidneys in infected mice and suppressed C. albicans virulence in the mouse model, Conclusi ons: Our results demonstrate that the function of the CaCla4p protein kinase is essential for virulence and morphological switching of C. al bicans in a mouse model. Thus, hyphal formation of C. albicans mediate d by CaClad4p may contribute to the pathogenicity of this dimorphic fu ngus, suggesting that regulators of morphological switching may be use ful targets for antifungal drugs.