Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status.
Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status.
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DOI：
10.1128/mbio.00115-22
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发表时间：
2022-04-26
期刊：
影响因子：
6.4
通讯作者：
Palmer, Glen E.
中科院分区：
文献类型：
--
作者：
Regan, Jessica;DeJarnette, Christian;Luna-Tapia, Arturo;Parker, Josie E.;Reitler, Parker;Barnett, Stacey;Tucker, Katie M.;Kelly, Steven L.;Palmer, Glen E.
关键词：
唑类抗真菌药抑制甾醇14α-脱甲基酶（S14 DM），该酶消耗细胞麦角甾醇并促进功能失调的脂质14α-甲基麦角甾-8，24（28）-二烯-3 β，6 α-二醇的合成，最终抑制生长。在唑类存在下，β-甾醇Δ 5，6-去饱和酶（Erg 3 p）（在S14 DM抑制后产生甾醇-二醇的酶）的突变增强了白色念珠菌的生长。然而，erg 3无效突变体对某些生理胁迫敏感，并且毒性低于野生型。这些适应性缺陷可能不利于患者内无效突变体的选择。本研究旨在探讨Erg 3 p活性与C.白念珠菌的致病性，以及唑类药物治疗的疗效。构建了产生不同水平ERG 3转录物的菌株的等基因组。甾醇组合物的分析证实了相应宽范围的Erg 3 p活性。表型分析显示，即使Erg 3 p活性的适度降低也足以大大增强C.白色念珠菌在氟康唑存在下的体外生长而不影响适合性。此外，即使低水平的Erg 3 p活性也足以支持C.白色念珠菌在播散性感染的小鼠模型中。最后，虽然氟康唑对免疫活性小鼠中所有菌株的抗真菌效果相似，但Erg 3 p活性与C.白细胞减少小鼠中的白色念珠菌耐受治疗。总的来说，这些结果确定了Erg 3 p活性的相对水平决定了唑类对C.并揭示了宿主免疫在确定这种耐药机制的临床影响中的至关重要性。
The azole antifungals inhibit sterol 14α-demethylase (S14DM), which depletes cellular ergosterol and promotes synthesis of the dysfunctional lipid 14α-methylergosta-8,24(28)-dien-3β,6α-diol, ultimately arresting growth. Mutations that inactivate sterol Δ5,6-desaturase (Erg3p), the enzyme that produces the sterol-diol upon S14DM inhibition, enhances Candida albicans growth in the presence of the azoles. However, erg3 null mutants are sensitive to some physiological stresses and can be less virulent than the wild type. These fitness defects may disfavor the selection of null mutants within patients. The objective of this study was to investigate the relationship between Erg3p activity, C. albicans pathogenicity, and the efficacy of azole therapy. An isogenic panel of strains was constructed that produce various levels of the ERG3 transcript. Analysis of the sterol composition confirmed a correspondingly wide range of Erg3p activity. Phenotypic analysis revealed that even moderate reductions in Erg3p activity are sufficient to greatly enhance C. albicans growth in the presence of fluconazole in vitro without impacting fitness. Moreover, even low levels of Erg3p activity are sufficient to support full virulence of C. albicans in the mouse model of disseminated infection. Finally, while the antifungal efficacy of fluconazole was similar for all strains in immunocompetent mice, there was an inverse correlation between Erg3p activity and the capacity of C. albicans to endure treatment in leukopenic mice. Collectively, these results establish that relative levels of Erg3p activity determine the antifungal efficacy of the azoles upon C. albicans and reveal the critical importance of host immunity in determining the clinical impact of this resistance mechanism.
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影响因子：
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