A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis.

Abstract

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, 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 upon Cu2+ coordination and cell surface association via a GPI 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 new role for LPMO-like proteins as a critical factor for Cu acquisition in fungal meningitis.