Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence.

Published

Journal Article

Copper (Cu) is an essential metal that is toxic at high concentrations. Thus, pathogens often rely on host Cu for growth, but host cells can hyperaccumulate Cu to exert antimicrobial effects. The human fungal pathogen Cryptococcus neoformans encodes many Cu-responsive genes, but their role in infection is unclear. We determined that pulmonary C. neoformans infection results in Cu-specific induction of genes encoding the Cu-detoxifying metallothionein (Cmt) proteins. Mutant strains lacking CMTs or expressing Cmt variants defective in Cu-coordination exhibit severely attenuated virulence and reduced pulmonary colonization. Consistent with the upregulation of Cmt proteins, C. neoformans pulmonary infection results in increased serum Cu concentrations and increases and decreases alveolar macrophage expression of the Cu importer (Ctr1) and ATP7A, a transporter implicated in phagosomal Cu compartmentalization, respectively. These studies indicate that the host mobilizes Cu as an innate antifungal defense but C. neoformans senses and neutralizes toxic Cu to promote infection.

Full Text

Duke Authors

Cited Authors

  • Ding, C; Festa, RA; Chen, Y-L; Espart, A; Palacios, Ò; Espín, J; Capdevila, M; Atrian, S; Heitman, J; Thiele, DJ

Published Date

  • March 13, 2013

Published In

Volume / Issue

  • 13 / 3

Start / End Page

  • 265 - 276

PubMed ID

  • 23498952

Pubmed Central ID

  • 23498952

Electronic International Standard Serial Number (EISSN)

  • 1934-6069

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2013.02.002

Language

  • eng

Conference Location

  • United States