近日，美国加州大学教授Hiten D. Madhani及其研究组的论文发现了一种侵袭性真菌病原体的表型景观揭示了其独特的生物学特性。相关论文于2025年6月11日发表于国际顶尖学术期刊《细胞》杂志上。
为了在全球范围内破译其生物学，该研究组构建了4328个基因缺失，并在141种不同生长限制的体外条件下和小鼠感染期间以极高的精度测量了每个突变的适应度。课题组研究人员根据基因的表型特征来定义功能模块。深入研究以两种方式利用这些数据。首先，课题组定义并研究了关键信号通路的新成分，揭示了模型酵母中不存在的后生动物样细胞机制。其次，课题组人员确定了环境适应机制，以提高C. neoformans的哺乳动物毒力，缺乏已知的动物宿主。他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阻力。
据介绍，新型隐球菌是真菌性脑膜炎最常见的病原体，也是世卫组织最优先考虑的真菌病原体。除了与模式真菌有远亲关系外，C. neoformans也是一个强大的实验系统，用于探索从专业模式酵母谱系中丢失的保守真核机制。
附：英文原文
Title: Phenotypic landscape of an invasive fungal pathogen reveals its unique biology
Author: Michael J. Boucher, Sanjita Banerjee, Meenakshi B. Joshi, Angela L. Wei, Matthew J. Nalley, Manning Y. Huang, Susan Lei, Massimiliano Ciranni, Andrew Condon, Andreas Langen, Thomas D. Goddard, Ippolito Caradonna, Alexi I. Goranov, Christina M. Homer, Yasaman Mortensen, Sarah Petnic, Morgann C. Reilly, Ying Xiong, Katherine J. Susa, Vito Paolo Pastore, Balyn W. Zaro, Hiten D. Madhani
Issue&Volume: 2025-06-11
Abstract: 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.
DOI: 10.1016/j.cell.2025.05.017
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00567-7