Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment.
Candida albicans, a clinically important dimorphic fungal pathogen that can evade immune attack by masking its cell wall beta-glucan from immune recognition, mutes protective host responses mediated by the Dectin-1 beta-glucan receptor on innate immune cells. Although the ability of C. albicans to switch between a yeast- or hyphal-form is a key virulence determinant, the role of each morphotype in beta-glucan masking during infection and treatment has not been addressed. Here, we show that during infection of mice, the C. albicans beta-glucan is masked initially but becomes exposed later in several organs. At all measured stages of infection, there is no difference in beta-glucan exposure between yeast-form and hyphal cells. We have previously shown that sub-inhibitory doses of the anti-fungal drug caspofungin can expose beta-glucan in vitro, suggesting that the drug may enhance immune activity during therapy. This report shows that caspofungin also mediates beta-glucan unmasking in vivo. Surprisingly, caspofungin preferentially unmasks filamentous cells, as opposed to yeast form cells, both in vivo and in vitro. The fungicidal activity of caspofungin in vitro is also filament-biased, as corroborated using yeast-locked and hyphal-locked mutants. The uncloaking of filaments is not a general effect of anti-fungal drugs, as another anti-fungal agent does not have this effect. These results highlight the advantage of studying host-pathogen interaction in vivo and suggest new avenues for drug development.
Wheeler
Robert T
RT
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America. robert.wheeler@umit.maine.edu
Kombe
Diana
D
Agarwala
Sudeep D
SD
Fink
Gerald R
GR
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D002176:Candida albicans / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy* / Q000276:immunology*; D000077336:Caspofungin; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use*; D000939:Epitopes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D054884:Host-Pathogen Interactions / Q000187:drug effects; D025301:Hyphae / Q000187:drug effects; D037181:Lectins, C-Type; D055666:Lipopeptides; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D047071:beta-Glucans / Q000378:metabolism*; D000099181:Dectin-1
D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D000939:Epitopes; D015725:Fluconazole; D037181:Lectins, C-Type; D055666:Lipopeptides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D047071:beta-Glucans; D000099181:Dectin-1; C045268:beta-glucan receptor