期刊
INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY
卷 309, 期 6, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.ijmm.2019.151330
关键词
ADH1; Candida albicans; Pathogenicity; Oxidative phosphorylation
资金
- National Natural Science Foundation of China [81471995/81171542]
- China Postdoctoral Science Foundation [2019M653291]
Objective: Alcohol dehydrogenase I is encoded by ADH1 in Candida albicans, and is one of the key enzymes in fungal metabolism by which it catalyzes the conversion from acetaldehyde to ethanol. The role of the associated protein Adh1p, encoded by ADHI in fungal pathogenicity has not been thoroughly studied despite its near ubiquity in the fungal kingdom. Using C. albicans as a model, this study proposes to determine the possible pathogenic roles for ADH1 and its possible underlying mechanisms. Methods: The SAT1 flipper strategy was used to construct the ADHI deletion mutant. Growth curves and spot assay were used to compare growth and cell viability of the mutant to wild type C. albicans. Three host model systems (infected mice, C. elegans, and G. mellonella) were used to investigate the effects of ADH1 deletion in vivo on C. albicans pathogenicity. Then, adhesion, hyphal formation, biofilm formation, cell surface hydrophobicity (CSH) and RT-qPCR were performed to investigate the effects of ADHI deletion in vitro on C. albicans virulence. Finally, Xfe 96 seahorse assay, ROS level, mitochondrial membrane potential, and intracellular ATP content were used to determine the effects of ADH1 deletion on bioenergetics. Results: ADH1 deletion has no effects on the growth and cell viability of C. albicans, but significantly prolongs survival time in each of the three host models, decreases fungal burden in kidney and liver, and lessens pathological tissue damage (P < 0.05). In addition, ADH1 deletion significantly increases CSH and reduces C. albicans virulence in terms of adhesion, hyphal formation and biofilm formation in accord with the downregulation of virulence-related genes such as ALS1, ALS3, HWP1, and CSH1 (P < 0.05). For bioenergetics, ADH1 deletion has no obvious effect on glycolysis, but a lack of ADHI significantly increases ROS levels and decreases mitochondrial membrane potential and intracellular ATP content even through the mitochondrial oxygen consumption rate and NADH/NAD(+) ratio are elevated (P < 0.05). Conclusion: Our results suggest that the fermentative enzyme ADHI is required for the pathogenicity of C. albicans under one of the presumed mechanisms viaits effects on oxidative phosphorylation activities in mitochondria.
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