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

Area of Science:

• Mycology
• Infectious Diseases
• Molecular Biology

Background:

• Cryptococcus neoformans causes lethal fungal meningitis, particularly in immunocompromised individuals.
• Copper acquisition is essential for C. neoformans virulence and brain colonization.
• While Ctr1 and Ctr4 mediate intracellular copper import, extracellular copper ligands remain largely uncharacterized.

Purpose of the Study:

• To identify and characterize novel extracellular factors involved in copper acquisition by C. neoformans.
• To elucidate the role of these factors in fungal pathogenesis and brain colonization.

Main Methods:

• Gene identification and characterization of BIM1 in C. neoformans.
• Analysis of bim1 mutant phenotypes under varying copper conditions.
• Investigation of Bim1 protein localization and function using biochemical assays.
• Assessment of C. neoformans brain colonization in a mouse infection model.

Main Results:

• A novel gene, BIM1, encoding a lytic polysaccharide monooxygenase (LPMO)-like protein, was identified and found to be induced during copper limitation.
• bim1 mutants exhibited significant copper deficiency, indicating Bim1's critical role in copper accumulation.
• Bim1 function in copper uptake is dependent on copper(II) coordination and cell-surface association via a glycophosphatidyl inositol anchor.
• Bim1 functions in concert with Ctr1 to facilitate copper uptake, and its expression drives brain colonization in vivo.

Conclusions:

• LPMO-like proteins, exemplified by Bim1, represent a critical, previously unrecognized factor for copper acquisition in C. neoformans.
• The Bim1-mediated copper acquisition pathway is essential for fungal meningitis pathogenesis and brain colonization.
• Targeting this pathway offers a potential strategy for combating cryptococcal meningitis.