PLoS Biol：黄广华等白色念珠菌形态转换研究获进展

形态转换对于病原真菌迅速适应宿主多变的微环境具有重要作用。白念珠菌（Candida albicans）是人体内一种重要的机会性致病真菌，通常共生于健康人体内不引起任何不良反应，但在免疫受损的人群中可能引起器官黏膜感染和危及生命的血液感染。近年来，由于广谱抗菌素的广泛使用，癌症化疗和器官移植等新的医疗技术的应用，艾滋病的流行和人口的老龄化，导致以白色念珠菌为主的真菌感染成为临床上日益严重的问题。

白色念珠菌既是人体共生菌又是病原体的两面性，是由其独特的生物学特征决定的，是与宿主相互作用中长期共进化的结果。白色念珠菌致病性与其形态发生和有性生殖密切相关。上世纪80年代，美国Soll实验室首次发现白色念珠菌能进行一种可逆且可遗传的形态转换，即“白菌-灰菌形态转换”。白菌和灰菌细胞在形态、毒性、对宿主免疫细胞的敏感性及交配能力等多个方面都有差异。长期以来，人们一直认为临床上只有小部分菌株（低于8%）能进行白菌-灰菌形态转换，这些菌株交配型都是纯合的（MTL， a/a或α/α）。而在临床上占主导地位的MTL杂合型（a/α）菌株，虽然其基因组中含有全部形态转换所必需的基因，但以前从未发现过有白菌向灰菌转换的现象。

最近，中科院微生物研究所黄广华课题组和白逢彦课题组合作研究发现，在模拟宿主环境条件下，白色念珠菌MTL杂合型菌株与纯合型菌株一样，也能进行白菌-灰菌形态转换。MTL杂合型菌株的灰菌菌落和细胞形态与纯合型菌株相似，且灰菌与白菌在不同小鼠感染模型下的毒性具有明显差异。进一步研究发现，转录因子Rfg1、Brg1和Efg1等作为负调控因子，Wor1、Wor2和Czf1等作为正调控因子，协同调控白菌-灰菌形态转换关键基因WOR1的表达，从而决定MTL杂合型菌株形态的建成。该研究揭示了白色念珠菌白菌-灰菌形态转换的普遍性特征，增进了对该菌宿主微环境适应、致病性和有性生殖中的认识，修改了白菌-灰菌形态转换调控理论，并为预防和治疗念珠菌病提供了新的思路，具有重要的临床意义。

该研究在“百人计划”和国家自然科学基金委相关项目资助下完成，并得到了微生物所张立新课题组和美国加州大学旧金山分校 Sandy Johnson实验室的支持。相关研究成果最近发表在国际杂志PLoS Biology上。

doi:10.1371/journal.pbio.1001525
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White-Opaque Switching in Natural MTLa/α Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis, and Sex

Jing Xie equal contributor, Li Tao equal contributor, Clarissa J. Nobile, Yaojun Tong, Guobo Guan, Yuan Sun, Chengjun Cao, Aaron D. Hernday, Alexander D. Johnson, Lixin Zhang, Feng-Yan Bai, Guanghua Huang

Phenotypic transitions play critical roles in host adaptation, virulence, and sexual reproduction in pathogenic fungi. A minority of natural isolates of Candida albicans, which are homozygous at the mating type locus (MTL, a/a or α/α), are known to be able to switch between two distinct cell types: white and opaque. It is puzzling that white-opaque switching has never been observed in the majority of natural C. albicans strains that have heterozygous MTL genotypes (a/α), given that they contain all of the opaque-specific genes essential for switching. Here we report the discovery of white-opaque switching in a number of natural a/α strains of C. albicans under a condition mimicking aspects of the host environment. The optimal condition for white-to-opaque switching in a/α strains of C. albicans is to use N-acetylglucosamine (GlcNAc) as the sole carbon source and to incubate the cells in 5% CO2. Although the induction of white-to-opaque switching in a/α strains of C. albicans is not as robust as in MTL homozygotes in response to GlcNAc and CO2, opaque cells of a/α strains exhibit similar features of cellular and colony morphology to their MTL homozygous counterparts. Like MTL homozygotes, white and opaque cells of a/α strains differ in their behavior in different mouse infection models. We have further demonstrated that the transcriptional regulators Rfg1, Brg1, and Efg1 are involved in the regulation of white-to-opaque switching in a/α strains. We propose that the integration of multiple environmental cues and the activation and inactivation of a set of transcriptional regulators controls the expression of the master switching regulator WOR1, which determines the final fate of the cell type in C. albicans. Our discovery of white-opaque switching in the majority of natural a/α strains of C. albicans emphasizes its widespread nature and importance in host adaptation, pathogenesis, and parasexual reproduction.

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