Comparative analysis of calcineurin signaling between Candida dubliniensis and Candida albicans

Abstract

Candida dubliniensis, an emerging fungal pathogen, is the closest known species to the established pathogenic species Candida albicans. Despite the fact that these two species share > 80% genome sequence identity, they exhibit distinct properties such as less hyphal growth, reduced pathogenicity and increased sensitivity to sodium stress and elevated temperatures in C. dubliniensis compared with C. albicans. It is, however, largely unknown whether signaling pathways are conserved in the two Candida species. Calcineurin signaling is known to be required for hyphal growth in Cryptococcus neoformans and Aspergillus fumigatus but remains elusive in C. albicans. Our recent study showed that calcineurin plays a clearly demonstrable role in controlling hyphal growth, drug tolerance and virulence in C. dubliniensis. Here, we extend our studies and show that calcineurin is conserved in controlling endoplasmic reticulum stress but distinct in governing pH homeostasis. Furthermore, we demonstrate that azole or echinocandin drugs in combination with the calcineurin inhibitor FK506 exhibit a synergistic effect against C. dubliniensis wild-type and echinocandin-resistant strains. The involvement of calcineurin in a variety of fungal virulence attributes and as a target for fungicidal synergism with azoles and echinocandins highlights the potential of combination therapy with calcineurin inhibitors for treating Candida infections.

Keywords: :

• Crz1
• Crz2
• ER stress
• hyphal growth
• pH homeostasis
• serum survival
• virulence

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Cecelia Shertz and Joanne Kingsbury for edits and comments on the manuscript, and David Perlin and Ana Alastruey-Izquierdo at the Public Health Research Institute Center of UMDNJ-New Jersey Medical School for the C. dubliniensis echinocandin- resistant strain DPL278. These studies were funded by a Duke University Chemistry Department Undergraduate Research Fellowship (J.Z.), the Center for AIDS Research (CFAR grant, 2P30 AI064518–06 to Y.-L.C.), NIH/NIAID R01 grant AI50438 (J.H.), and pilot funds from Merck and Co. Inc. and Astellas Pharma Inc. (J.H. and Y.-L.C.).