Identification of 10 genes on Candida albicans chromosome 5 that control surface exposure of the immunogenic cell wall epitope β-glucan and cell wall remodeling in caspofungin-adapted mutants.
Identification of 10 genes on Candida albicans chromosome 5 that control surface exposure of the immunogenic cell wall epitope β-glucan and cell wall remodeling in caspofungin-adapted mutants.
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DOI：
10.1128/spectrum.03295-23
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发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
白色念珠菌是正常微生物区系的一部分；然而，它可以在免疫受损的人中引起浅表和危及生命的感染。随着棘球酵母菌(ECN)类药物用于治疗念珠菌病的增加，对ECN的耐药性也在出现。我们确定了白念珠菌5号染色体(CH5)上的10个基因同时下调，以降低对ECN卡泊芬净的易感性。独立的基因敲除实验表明，这些基因总体上作用于降低细胞壁中1，3-β-葡聚糖的水平，改变甘露聚糖和甲壳素的水平，并影响FKS基因的表达。重要的是，CH5上的10个基因增加或减少了免疫原性表位1，3-β-葡聚糖的表面暴露。我们的数据显示了以前未鉴定的orf19.970和orf19.4149.1的功能，其中orf19.970没有人类同源基因。我们的数据还表明，DUS4、RPS25B、UAP1、URA7、RPO26、HAS1和CKS1基因具有新的功能，而CHT2作为ECN易感性的负调控因子的功能已经被确定。重要的是，上述基因中有一半是必需的；因此，对中枢神经系统的适应涉及到不可或缺的过程。我们的结果表明，一组新的基因协同工作，控制对中枢神经系统的适应，并指向潜在的新药靶点。念珠菌感染在免疫功能受损的人中往往是致命的，每年导致数千人死亡。卡泊芬净已被证明是一种出色的抗念珠菌药物，现在是感染的一线治疗药物。然而，正如预期的那样，耐药病例的数量正在增加；因此，需要新的治疗方式。我们正在确定导致药物敏感性降低的代谢途径，以确定促进临床耐药演变的机制。这项研究扩大了对调节药物敏感性的基因的理解，并为新型抗真菌药物的开发提供了新的靶点。
Candida albicans is part of normal microbiota; however, it can cause superficial and life-threatening infections in immune-compromised individuals. As the use of drugs from the echinocandin (ECN) class for the treatment of candidiasis is increasing, resistance against ECNs is also emerging. We identified 10 genes on C. albicans chromosome 5 (Ch5) that are simultaneously downregulated to decrease susceptibility to ECN caspofungin. Independent knock-out experiments demonstrated that these genes act overall to decrease the 1,3-β-glucan level in the cell wall, change levels of mannan and chitin, and affect expression of FKS genes. Importantly, 10 genes on Ch5 increase or decrease surface exposure of the immunogenic epitope 1,3-β-glucan. Our data indicate functions for previously uncharacterized orf19.970 and orf19.4149.1, of which orf19.970 has no human ortholog. Our data also indicate new functions for the genes DUS4, RPS25B, UAP1, URA7, RPO26, HAS1, and CKS1, whereas the function of CHT2 as a negative regulator of ECN susceptibility has been previously established. Importantly, half of the above genes are essential; hence, indispensable processes are involved in the adaptation to ECNs. Our results suggest that a novel group of genes works in concert to control adaptation to ECNs and point to potential new drug targets. Candida infections are often fatal in immuno-compromised individuals, resulting in many thousands of deaths per year. Caspofungin has proven to be an excellent anti-Candida drug and is now the frontline treatment for infections. However, as expected, the number of resistant cases is increasing; therefore, new treatment modalities are needed. We are determining metabolic pathways leading to decreased drug susceptibility in order to identify mechanisms facilitating evolution of clinical resistance. This study expands the understanding of genes that modulate drug susceptibility and reveals new targets for the development of novel antifungal drugs.
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影响因子：
6.7
作者：
Blankenship JR;Fanning S;Hamaker JJ;Mitchell AP
通讯作者：
Mitchell AP
影响因子：
4.5
作者：
通讯作者：
--
影响因子：
28.3
作者：
Ballou ER;Avelar GM;Childers DS;Mackie J;Bain JM;Wagener J;Kastora SL;Panea MD;Hardison SE;Walker LA;Erwig LP;Munro CA;Gow NA;Brown GD;MacCallum DM;Brown AJ
通讯作者：
Brown AJ
影响因子：
5.2
作者：
Godoy, Pablo;Darlington, Peter John;Whiteway, Malcolm
通讯作者：
Whiteway, Malcolm
缺氧通过通过线粒体和cAMP蛋白激酶A信号转导在白色念珠菌细胞表面上触发β-葡聚糖掩膜来促进免疫逃避。
影响因子：
6.4
作者：
Pradhan A;Avelar GM;Bain JM;Childers DS;Larcombe DE;Netea MG;Shekhova E;Munro CA;Brown GD;Erwig LP;Gow NAR;Brown AJP
通讯作者：
Brown AJP