Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Tian-Shu Sun, Xiao Ju, Hui-Ling Gao, Tao Wang, Dennis J. Thiele, Jia-Yi Li, Zhan-You Wang () and Chen Ding ()
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Tian-Shu Sun: College of Life and Health Sciences, Northeastern University
Xiao Ju: College of Life and Health Sciences, Northeastern University
Hui-Ling Gao: College of Life and Health Sciences, Northeastern University
Tao Wang: College of Life and Health Sciences, Northeastern University
Dennis J. Thiele: Duke University School of Medicine
Jia-Yi Li: College of Life and Health Sciences, Northeastern University
Zhan-You Wang: College of Life and Health Sciences, Northeastern University
Chen Ding: College of Life and Health Sciences, Northeastern University

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6550

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