title: Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis.
abstract: Copper homeostasis is important for virulence of the fungus Cryptococcus neoformans, which can cause lethal meningoencephalitis in humans. Cryptococcus cells encounter high copper levels in the lung, where infection is initiated, and low copper levels in the brain. Here we demonstrate that two Cryptococcus copper transporters, Ctr1 and Ctr4, differentially influence fungal survival during pulmonary infection and the onset of meningoencephalitis. Protein Ctr1 is rapidly degraded under the high-copper conditions found in infected lungs, and its loss has no effect in fungal virulence in mice. By contrast, deleting CTR4 results in a hypervirulent phenotype. Overexpressing either Ctr1 or Ctr4 leads to profound reductions in fungal burden in the lung. However, during the onset of meningoencephalitis, expression of the copper transporters is induced and is critical for Cryptococcus virulence. Our work demonstrates that the fungal cells switch between copper detoxification and acquisition to address different copper stresses in the host.
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Tian-Shu
authors.initials: TS
authors.lastname: Sun
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ju
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Gao
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
authors.affiliation: 1] College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China [2] Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 22184 Lund, Sweden.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, ShenYang, LiaoNing 110015, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
mesh_terms: D000818:Animals; D001921:Brain / Q000382:microbiology / Q000473:pathology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D003300:Copper / Q000378:metabolism*; D003453:Cryptococcosis / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000378:metabolism / Q000472:pathogenicity*; D005260:Female; D006706:Homeostasis; D017136:Ion Transport / Q000235:genetics*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008590:Meningoencephalitis / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL
chemical_list: D027682:Cation Transport Proteins; D003300:Copper