Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence

Chen Ding, Richard A. Festa, Ying Lien Chen, Anna Espart, Òscar Palacios, Jordi Espín, Mercè Capdevila, Sílvia Atrian, Joseph Heitman, Dennis J. Thiele

Research output: Contribution to journalArticleResearchpeer-review

106 Citations (Scopus)

Abstract

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. © 2013 Elsevier Inc.
Original languageEnglish
Pages (from-to)265-276
JournalCell Host and Microbe
Volume13
Issue number3
DOIs
Publication statusPublished - 13 Mar 2013

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