We are studying the function of host extracellular matrix components in the pathogenesis of Candida albicans. Using in vitro assays to quantify adhesion of C. albicans to immobilized fibronectin and its proteolytic and recombinant fragments and to evaluate binding of soluble fibronectin to C. albicans in suspension, we found that interactions of fibronectin with this organism are not mediated by the Arg-Gly-Asp integrin recognition sequence of fibronectin. High affinity binding, observed following grown in complex medium, is mediated by the collagen-binding domain of fibronectin, which is recognized by a high affinity receptor and the cell-binding domain of fibronectin, which engages a low affinity receptor. Expression of both fibronectin receptors is tightly regulated by growth conditions. We identified hemoglobin as a highly specific inducer of the low affinity receptor. Hemoglobin-inducible binding was observed in all clinical isolates of C. albicans and in other members of the Candida genus. The response to hemoglobin is mediated by a low affinity hemoglobin receptor on C. albicans. This activation may play an important role in pathogenesis, since only pathogenic strains of C. albicans express hemolytic activity. Hemoglobin may therefore be a host environmental cue that triggers extracellular matrix receptor expression at a septic site. Inhibitors of this activation process may decrease the pathogenicity of C. albicans. We have identified several genes whose expression is induced by hemoglobin. One of these encodes a gene related to YDL166c in S. cerevisiae. Disruption of this gene in C. albicans was lethal for growth, and the heterozygous mutant was impaired in some responses to stress. Remarkably, the heterozygous mutant displayed high frequency phase switching to the opaque form, which is the mating competent form of C. albicans. We found that this switch was controlled through regulation of the mating type locus alpha genes. Opaque cells of the heterozygous mutant were also competent to mate with a opaque MTLa cells. This identifies HBR1 as an important regulatory gene for the MTL alpha locus and is the first demonstration that mating can occur in C. albicans without disruption of the MTL locus.
