Molecular Microbiology and Immunology Department, Brown University, Providence, RI 02912, USA.
Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA.
Cell Host Microbe. 2019 Mar 13;25(3):418-431.e6. doi: 10.1016/j.chom.2019.01.005. Epub 2019 Feb 26.
Candida albicans is a commensal fungus of human gastrointestinal and reproductive tracts, but also causes life-threatening systemic infections. The balance between colonization and pathogenesis is associated with phenotypic plasticity, with alternative cell states producing different outcomes in a mammalian host. Here, we reveal that gene dosage of a master transcription factor regulates cell differentiation in diploid C. albicans cells, as EFG1 hemizygous cells undergo a phenotypic transition inaccessible to "wild-type" cells with two functional EFG1 alleles. Notably, clinical isolates are often EFG1 hemizygous and thus licensed to undergo this transition. Phenotypic change corresponds to high-frequency loss of the functional EFG1 allele via de novo mutation or gene conversion events. This phenomenon also occurs during passaging in the gastrointestinal tract with the resulting cell type being hypercompetitive for commensal and systemic infections. A "two-hit" genetic model therefore underlies a key phenotypic transition in C. albicans that enables adaptation to host niches.
白色念珠菌是人体胃肠道和生殖系统的共生真菌，但也会导致危及生命的全身感染。定植和发病之间的平衡与表型可塑性有关，不同的细胞状态在哺乳动物宿主中产生不同的结果。在这里，我们揭示了一个主转录因子的基因剂量调节了二倍体 C. albicans 细胞的细胞分化，因为 EFG1 半合子细胞经历了一种“野生型”细胞无法进入的表型转变，“野生型”细胞有两个功能正常的 EFG1 等位基因。值得注意的是，临床分离株通常是 EFG1 半合子，因此可以进行这种转变。表型变化对应于功能性 EFG1 等位基因通过新突变或基因转换事件的高频丢失。这种现象也发生在胃肠道的传代过程中，导致细胞类型对共生和全身感染具有超竞争力。因此，“双打击”遗传模型是 C. albicans 中关键表型转变的基础，使它能够适应宿主小生境。
