Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK506 and Cyclosporine A. In the pathogenic mucoralean fungus Mucor circinelloides, calcineurin mutation or inhibition confers a yeast-locked phenotype indicating that calcineurin governs the dimorphic transition. Genetic analysis in this study reveals that two calcineurin A catalytic subunits (out of three) are functionally diverged. Homology modeling illustrates modes of resistance resulting from amino substitutions in the interface between each calcineurin subunit and the inhibitory drugs. In addition, we show how the dimorphic transition orchestrated by calcineurin programs different outcomes during host-pathogen interactions. For example, when macrophages phagocytose Mucor yeast, subsequent phagosomal maturation occurs, indicating host cells respond appropriately to control the pathogen. On the other hand, upon phagocytosis of spores, macrophages fail to form mature phagosomes. Cytokine production from immune cells differs following exposure to yeast versus spores (which germinate into hyphae). Thus, the morphogenic transition can be targeted as an efficient treatment option against Mucor infection. In addition, genetic analysis (including gene disruption and mutational studies) further strengthens the understanding of calcineurin and provides a foundation to develop antifungal agents targeting calcineurin to deploy against Mucor and other pathogenic fungi.
Bibliographical note© 2015 John Wiley & Sons Ltd.
We thank Anna Averette, Raul Salinas and Valerie Lapham for technical support. We are indebted to Heesoo Park and Ci Fu for discussions and critical reading and Tony Adinolfi for his support of this study. We thank Keisha Findley, Clayton Deming and Julie Segre for providing the Mcc isolate 1006PhL, Bill Steinbach and Praveen Juvvadi for providing the A. fumigatus strain AF293. This work was supported by NIH/NIAID R01 AI50438-10 to J.H., and by R21 award AI85331 and an Astellas IIT award to S.C.L. and J.H., NIH/NIAID R01 AI88100 to M.L.S., and The Butler Pioneer Award to D.C.K.
- diomorphic transitions
- antifungal transitions
- pathogen interactions
- Mucor cirinelloides