title: Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence.
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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.forename: Richard A
authors.initials: RA
authors.lastname: Festa
authors.forename: Ying-Lien
authors.initials: YL
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Espart
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Palacios
authors.forename: Jordi
authors.initials: J
authors.lastname: Espín
authors.forename: Mercè
authors.initials: M
authors.lastname: Capdevila
authors.forename: Sílvia
authors.initials: S
authors.lastname: Atrian
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D001692:Biological Transport; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D003300:Copper / Q000378:metabolism*; D003453:Cryptococcosis / Q000378:metabolism / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D003300:Copper; D008668:Metallothionein