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Deletion of ADA2 Increases Antifungal Drug Susceptibility and Virulence in Candida glabrata.


ABSTRACT: Candida glabrata, the second most frequent cause of candidiasis after Candida albicans, is an emerging human fungal pathogen that is intrinsically drug tolerant. Currently, studies of C. glabrata genes involved in drug tolerance are limited. Ada2, a component serving as a transcription adaptor of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, is required for antifungal drug tolerance and virulence in C. albicans However, its roles in C. glabrata remain elusive. In this study, we found that ada2 mutants demonstrated severe growth defects at 40°C but only mild defects at 37°C or 25°C. In addition, C. glabrata ada2 mutants exhibited pleiotropic phenotypes, including susceptibility to three classes of antifungal drugs (i.e., azoles, echinocandins, and polyenes) and cell wall-perturbing agents but resistance to the endoplasmic reticulum stressor tunicamycin. According to RNA sequence analysis, the expression of 43 genes was downregulated and the expression of 442 genes was upregulated in the ada2 mutant compared to their expression in the wild type. C. glabrata ADA2, along with its downstream target ERG6, controls antifungal drug tolerance and cell wall integrity. Surprisingly, ada2 mutants were hypervirulent in a murine model of systemic infection, possibly due to the upregulation of multiple adhesin-like genes, increased agar invasion, and overstimulation of murine tumor necrosis factor alpha production.

SUBMITTER: Yu SJ 

PROVIDER: S-EPMC5826168 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Deletion of <i>ADA2</i> Increases Antifungal Drug Susceptibility and Virulence in Candida glabrata.

Yu Shang-Jie SJ   Chang Ya-Lin YL   Chen Ying-Lien YL  

Antimicrobial agents and chemotherapy 20180223 3


<i>Candida glabrata</i>, the second most frequent cause of candidiasis after <i>Candida albicans</i>, is an emerging human fungal pathogen that is intrinsically drug tolerant. Currently, studies of <i>C. glabrata</i> genes involved in drug tolerance are limited. Ada2, a component serving as a transcription adaptor of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, is required for antifungal drug tolerance and virulence in <i>C. albicans</i> However, its roles in <i>C. glabrata</i> remain elus  ...[more]

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