Histidine kinase, two-component signal transduction proteins of Candida albicans and the pathogenesis of candidosis

Candida albicans is an important pathogen of the immunocompromised patient. Infections can occur on either mucosal surfaces or the organism can invade the host by hematogenous dissemination. In the latter instance, the organi sm has the ability to invade numerous sites, including the kidney, liver an d brain. Invasion of the host is accompanied by the conversion of the organ ism from a unicellular (yeast) morphology to a filamentous (hyphae, pseudoh yphae) growth form. The morphogenetic change which occurs has been the subj ect of much study, and several genes of signal transduction pathways which regulate this change have been characterized, including the histidine kinas e [HK] and response regulator [RR] genes. The HKs of C. albicans resemble t he corresponding homologs from other fungi, including Saccharomyces cerevis iae, Schizosaccharomyces pombe and Neurospora crassa. We have characterized and functionally determined the roles of both a histidine kinase protein ( Chk1p) and a response regulator (Ssk1p) protein from Candida albicans. Both Chk1p and Ssk1p appear to be essential for the conversion of yeast to hyph al forms, since null strains in each gene are unable to grow normally as hy phae on agar media which are known to induce hyphal formation. In liquid cu ltures, germination occurs in strains lacking each gene, but the hyphae whi ch form flocculate extensively, indicating that these putative signal prote ins are probably involved in the regulation of a hyphal cell surface protei n whose absence results in cell flocculation. Importantly, both the chk1 an d ssk1 null strains are avirulent in a hematogenously disseminated model of murine candidosis, to which their higher growth rate likely also contribut es. Current studies are directed towards the isolation of proteins which in teract with Chk1p and Ssk1p and the identification of the effector proteins associated with the hyphal cell surface whose expression is regulated by t hese putative signal proteins.