Requirement for Candida albicans sun41 in biofilm formation and virulence
Requirement for Candida albicans sun41 in biofilm formation and virulence
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DOI：
10.1128/ec.00314-07
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发表时间：
2007-11-01
期刊：
影响因子：
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通讯作者：
Mitchell, Aaron P.
中科院分区：
文献类型：
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作者：
Norice, Carmelle T.;Smith, Frank J., Jr.;Mitchell, Aaron P.
白色念珠菌的细胞壁处于致病性和治疗性的十字路口。它有助于通过粘附和入侵的致病性;它是化学和免疫抗真菌策略的目标。我们已经开始解剖细胞壁功能，通过有针对性的插入突变的细胞壁相关基因。在25个这样的基因中，我们无法在4个中产生纯合突变，它们可能是生存所必需的。我们在剩下的21个基因中创造了纯合突变。SUN 41、Orf19.5412、Orf19.1277、MSB 2、Orf19.3869和WSC 1中的插入突变引起对细胞壁抑制剂卡泊芬净的超敏反应，而两种不同的ecm 33插入引起轻度卡泊芬净耐药。SUN 41和Orf19.5412的插入突变导致生物膜缺陷。通过分析纯合sun 41 Delta/sun 41 Delta缺失突变体和sun 41 Delta/sun 41 Delta + pSUN 41互补菌株，我们证实了Sun 41是生物膜形成和正常卡泊芬净耐受性所需的。sun 41 Delta/sun 41 Delta突变体改变了四个细胞壁损伤反应基因的表达，因此表明它患有细胞壁结构缺陷。Sun 41是诱导疾病所必需的，因为该突变体在播散性和口咽念珠菌病的小鼠模型中被严重减弱。虽然该突变体产生异常菌丝，但与许多其他菌丝缺陷突变体不同，它在损伤内皮或上皮细胞方面没有缺陷。我们认为sun 41 Delta/sun 41 Delta细胞壁缺陷是其毒力减弱的主要原因。Sun 41作为一种具有预测葡萄糖苷酶活性的小的真菌表面蛋白，代表了一个有前途的治疗靶点。
The cell wall of Candida albicans lies at the crossroads of pathogenicity and therapeutics. It contributes to pathogenicity through adherence and invasion; it is the target of both chemical and immunological antifungal strategies. We have initiated a dissection of cell wall function through targeted insertional mutagenesis of cell wall-related genes. Among 25 such genes, we were unable to generate homozygous mutations in 4, and they may be essential for viability. We created homozygous mutations in the remaining 21 genes. Insertion mutations in SUN41, Orf19.5412, Orf19.1277, MSB2, Orf19.3869, and WSC1 caused hypersensitivity to the cell wall inhibitor caspofungin, while two different ecm33 insertions caused mild caspofungin resistance. Insertion mutations in SUN41 and Orf19.5412 caused biofilm defects. Through analysis of homozygous sun41 Delta/sun41 Delta deletion mutants and sun41 Delta/sun41 Delta + pSUN41 -complemented strains, we verified that Sun41 is required for biofilm formation and normal caspofungin tolerance. The sun41 Delta/sun41 Delta mutant had altered expression of four cell wall damage response genes, thus suggesting that it suffers a cell wall structural defect. Sun41 is required for inducing disease, because the mutant was severely attenuated in mouse models of disseminated and oropharyngeal candidiasis. Although the mutant produced aberrant hyphae, it had no defect in damaging endothelial or epithelial cells, unlike many other hypha-defective mutants. We suggest that the sun41 Delta/sun41 Delta cell wall defect is the primary cause of its attenuated virulence. As a small fungal surface protein with predicted glucosidase activity, Sun41 represents a promising therapeutic target.