title: Calcineurin is required for pseudohyphal growth, virulence, and drug resistance in Candida lusitaniae.
abstract: Candida lusitaniae is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other Candida species, C. lusitaniae is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of C. lusitaniae including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a C. albicans Crz1 homolog acting as a downstream target of calcineurin, are required for C. lusitaniae pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in C. lusitaniae but hyphal growth is fundamental to C. albicans virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in C. lusitaniae. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant C. lusitaniae clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant C. lusitaniae infections.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Fitz Gerald S
authors.initials: FG
authors.lastname: Silao
authors.forename: Ursela G
authors.initials: UG
authors.lastname: Bigol
authors.forename: Alice Alma C
authors.initials: AA
authors.lastname: Bungay
authors.forename: Marilou G
authors.initials: MG
authors.lastname: Nicolas
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: Ying-Lien
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002175:Candida / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity* / Q000648:ultrastructure; D002176:Candida albicans / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D000077336:Caspofungin; D002473:Cell Wall / Q000187:drug effects / Q000648:ultrastructure; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal / Q000187:drug effects; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D025301:Hyphae / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D007634:Keratitis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D055666:Lipopeptides; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D044967:Serum; D014774:Virulence / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D019703:Calcineurin; D000077336:Caspofungin; D002118:Calcium