Differential regulation of the transcriptional repressor NRG1 accounts for altered host-cell interactions in Candida albicans and Candida dubliniensis

Candida dubliniensis is genetically closely related to Candida albicans, but causes fewer infections in humans and exhibits reduced virulence and filamentation in animal models of infection. We investigated the role of the C. dubliniensis transcriptional repressor-encoding gene CdNRG1 in regulating this phenotype. Deletion of both copies of CdNRG1 increased the formation of true hyphae by C. dubliniensis in response to serum, exogenous cAMP and CO2. In addition, deletion of CdNRG1 greatly enhanced filamentation and survival of C. dubliniensis in co-culture with murine macrophages. In the reconstituted human oral epithelium infection model, the nrg1 Delta mutant caused increased tissue damage relative to the wild-type strain. However, deletion of CdNRG1 did not change the virulence of C. dubliniensis in the systemic mouse model of infection. The increased rate of hypha formation in C. albicans relative to C. dubliniensis in response to phagocytosis by macrophages and serum was associated with rapid downregulation of NRG1 expression in C. albicans. This study demonstrates that the reduced virulence and host cell damage elicited by C. dubliniensis may in part be due to the inability of this species to modulate NRG1 expression in response to the same environmental signals that promote filamentation in C. albicans.