形態(tài)轉(zhuǎn)換對(duì)于病原真菌迅速適應(yīng)宿主多變的微環(huán)境具有重要作用,。白念珠菌（Candida albicans）是人體內(nèi)一種重要的機(jī)會(huì)性致病真菌,，通常共生于健康人體內(nèi)不引起任何不良反應(yīng),，但在免疫受損的人群中可能引起器官黏膜感染和危及生命的血液感染。近年來(lái),，由于廣譜抗菌素的廣泛使用,，癌癥化療和器官移植等新的醫(yī)療技術(shù)的應(yīng)用，艾滋病的流行和人口的老齡化,，導(dǎo)致以白色念珠菌為主的真菌感染成為臨床上日益嚴(yán)重的問(wèn)題,。
白色念珠菌既是人體共生菌又是病原體的兩面性，是由其獨(dú)特的生物學(xué)特征決定的,，是與宿主相互作用中長(zhǎng)期共進(jìn)化的結(jié)果,。白色念珠菌致病性與其形態(tài)發(fā)生和有性生殖密切相關(guān)。上世紀(jì)80年代,，美國(guó)Soll實(shí)驗(yàn)室首次發(fā)現(xiàn)白色念珠菌能進(jìn)行一種可逆且可遺傳的形態(tài)轉(zhuǎn)換,，即“白菌-灰菌形態(tài)轉(zhuǎn)換”。白菌和灰菌細(xì)胞在形態(tài),、毒性,、對(duì)宿主免疫細(xì)胞的敏感性及交配能力等多個(gè)方面都有差異。長(zhǎng)期以來(lái),，人們一直認(rèn)為臨床上只有小部分菌株（低于8%）能進(jìn)行白菌-灰菌形態(tài)轉(zhuǎn)換，這些菌株交配型都是純合的（MTL,， a/a或α/α）,。而在臨床上占主導(dǎo)地位的MTL雜合型（a/α）菌株，雖然其基因組中含有全部形態(tài)轉(zhuǎn)換所必需的基因,，但以前從未發(fā)現(xiàn)過(guò)有白菌向灰菌轉(zhuǎn)換的現(xiàn)象,。
最近，中科院微生物研究所黃廣華課題組和白逢彥課題組合作研究發(fā)現(xiàn),，在模擬宿主環(huán)境條件下,，白色念珠菌MTL雜合型菌株與純合型菌株一樣，也能進(jìn)行白菌-灰菌形態(tài)轉(zhuǎn)換,。MTL雜合型菌株的灰菌菌落和細(xì)胞形態(tài)與純合型菌株相似,，且灰菌與白菌在不同小鼠感染模型下的毒性具有明顯差異。進(jìn)一步研究發(fā)現(xiàn),，轉(zhuǎn)錄因子Rfg1,、Brg1和Efg1等作為負(fù)調(diào)控因子，Wor1,、Wor2和Czf1等作為正調(diào)控因子,，協(xié)同調(diào)控白菌-灰菌形態(tài)轉(zhuǎn)換關(guān)鍵基因WOR1的表達(dá)，從而決定MTL雜合型菌株形態(tài)的建成。該研究揭示了白色念珠菌白菌-灰菌形態(tài)轉(zhuǎn)換的普遍性特征,，增進(jìn)了對(duì)該菌宿主微環(huán)境適應(yīng),、致病性和有性生殖中的認(rèn)識(shí)，修改了白菌-灰菌形態(tài)轉(zhuǎn)換調(diào)控理論,，并為預(yù)防和治療念珠菌病提供了新的思路,，具有重要的臨床意義。
該研究在“百人計(jì)劃”和國(guó)家自然科學(xué)基金委相關(guān)項(xiàng)目資助下完成,，并得到了微生物所張立新課題組和美國(guó)加州大學(xué)舊金山分校 Sandy Johnson實(shí)驗(yàn)室的支持,。相關(guān)研究成果最近發(fā)表在國(guó)際雜志PLoS Biology上。（生物谷Bioon.com）
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.
