Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients.

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Serval ID
serval:BIB_FC219731F9DA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients.
Journal
Journal of Antimicrobial Chemotherapy
Author(s)
Siikala Emilia, Rautemaa Riina, Richardson Malcolm, Saxen Harri, Bowyer Paul, Sanglard Dominique
ISSN
1460-2091[electronic], 0305-7453[linking]
Publication state
Published
Issued date
2010
Volume
65
Number
12
Pages
2505-2513
Language
english
Abstract
Objectives: Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) suffer from chronic candidosis caused mainly by Candida albicans, and repeated courses of azole antifungals have led to the development of resistance in the APECED patient population in Finland. The aim of our study was to address whether the patients are persistently colonized with the same or genetically closely related strains, whether epidemic strains are present and which molecular mechanisms account for azole resistance.
Methods: Sets of C. albicans (n?=?19) isolates from nine APECED patients reported with decreased susceptibility to fluconazole isolated up to 9 years apart were included. The strains were typed by multilocus sequence typing. CDR1/2, MDR1 and ERG11 mRNA expression was analysed by northern blotting and Cdr1, Cdr2 and Mdr1 protein expression by western blotting, and TAC1 and ERG11 genes were sequenced. Results: All seven patients with multiple C. albicans isolates analysed were persistently colonized with the same or a genetically closely related strain for a mean of 5 years. All patients were colonized with different strains and no epidemic strains were found. The major molecular mechanisms behind the azole resistance were mutations in TAC1 contributing to overexpression of CDR1 and CDR2. Six new TAC1 mutations were found, one of which (N740S) is likely to be a gain-of-function mutation. Most isolates were found to have gained multiple TAC1 and ERG11 point mutations.
Conclusions: Despite clinically successful treatment leading to relief of symptoms, colonization by C. albicans strains is persistent within APECED patients. Microevolution and point mutations occur within strains, leading to the development of azole-resistant isolates.
Keywords
Chronic Oral Candidosis, Candidosis, CMC, Fluconazole, Resistance, TAC1, CDR1, CDR2, Chronic Mucocutaneous Candidiasis, HIV-Infected Patients, Syndrome Type-I, Fluconazole Resistance, Antifungal Agents, Decreased Susceptibility, Amphotericin-B, Transporters, Locus, Promoter
Pubmed
Web of science
Open Access
Yes
Create date
09/12/2010 10:51
Last modification date
25/09/2019 7:11
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