Boucher Michael J, Banerjee Sanjita, Joshi Meenakshi B, Wei Angela L, Nalley Matthew J, Huang Manning Y, Lei Susan, Ciranni Massimiliano, Condon Andrew, Langen Andreas, Goddard Thomas D, Caradonna Ippolito, Goranov Alexi I, Homer Christina M, Mortensen Yasaman, Petnic Sarah, Reilly Morgann C, Xiong Ying, Susa Katherine J, Pastore Vito Paolo, Zaro Balyn W, Madhani Hiten D
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16145 Genoa, Italy.
Cell. 2025 Jun 9. doi: 10.1016/j.cell.2025.05.017.
Cryptococcus neoformans is the most common cause of fungal meningitis and the top-ranking WHO fungal priority pathogen. Only distantly related to model fungi, C. neoformans is also a powerful experimental system for exploring conserved eukaryotic mechanisms lost from specialist model yeast lineages. To decipher its biology globally, we constructed 4,328 gene deletions and measured-with exceptional precision-the fitness of each mutant under 141 diverse growth-limiting in vitro conditions and during murine infection. We defined functional modules by clustering genes based on their phenotypic signatures. In-depth studies leveraged these data in two ways. First, we defined and investigated new components of key signaling pathways, which revealed metazoan-like cellular machinery not present in model yeasts. Second, we identified environmental adaptation mechanisms repurposed to promote mammalian virulence by C. neoformans, which lacks a known animal reservoir. Our work provides an unprecedented resource for deciphering a deadly human pathogen.
新型隐球菌是真菌性脑膜炎最常见的病因，也是世界卫生组织真菌重点病原体之首。新型隐球菌与模式真菌的亲缘关系较远，它也是一个强大的实验系统，用于探索在专门的模式酵母谱系中丢失的保守真核生物机制。为了全面解析其生物学特性，我们构建了4328个基因缺失突变体，并以极高的精度测量了每个突变体在141种不同的体外生长限制条件下以及小鼠感染过程中的适应性。我们根据基因的表型特征对基因进行聚类，从而定义了功能模块。深入研究从两个方面利用了这些数据。首先，我们定义并研究了关键信号通路的新组成部分，这些研究揭示了模式酵母中不存在的后生动物样细胞机制。其次，我们确定了新型隐球菌重新利用以促进其哺乳动物毒力的环境适应机制，新型隐球菌没有已知的动物宿主。我们的工作为破译一种致命的人类病原体提供了前所未有的资源。
