Infection by the fungal pathogen Cryptococcus neoformans causes lethal meningitis, primarily in immune-compromised individuals. Colonization of the brain by C. neoformans is dependent on copper (Cu) acquisition from the host, which drives critical virulence mechanisms. While C. neoformans Cu⁺ import and virulence are dependent on the Ctr1 and Ctr4 proteins, little is known concerning extracellular Cu ligands that participate in this process. We identified a C. neoformans gene, BIM1, that is strongly induced during Cu limitation and which encodes a protein related to lytic polysaccharide monooxygenases (LPMOs). Surprisingly, bim1 mutants are Cu deficient, and Bim1 function in Cu accumulation depends on Cu²⁺ coordination and cell-surface association via a glycophosphatidyl inositol anchor. Bim1 participates in Cu uptake in concert with Ctr1 and expression of this pathway drives brain colonization in mouse infection models. These studies demonstrate a role for LPMO-like proteins as a critical factor for Cu acquisition in fungal meningitis.

真菌病原体新型隐球菌感染会导致致命性脑膜炎，主要发生在免疫功能低下的个体中。新型隐球菌在大脑中的定殖依赖于从宿主获取铜 (Cu)，这驱动了关键的毒力机制。虽然新型隐球菌Cu ⁺输入和毒力依赖于 Ctr1 和 Ctr4 蛋白，但对于参与这一过程的细胞外 Cu 配体知之甚少。我们鉴定了一种新型隐球菌基因BIM1 ，该基因在 Cu 限制期间被强烈诱导，并且编码与裂解多糖单加氧酶 (LPMO) 相关的蛋白质。令人惊讶的是， bim1突变体缺乏 Cu，并且 Bim1 在 Cu 积累中的功能取决于 Cu ²⁺配位和通过糖磷脂酰肌醇锚定的细胞表面关联。 Bim1 与 Ctr1 协同参与铜的吸收，并且该通路的表达驱动小鼠感染模型中的大脑定植。这些研究证明了 LPMO 样蛋白作为真菌性脑膜炎中铜获取的关键因素。