Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans.
The study of regulatory networks in human pathogens such as Cryptococcus neoformans provides insights into host-pathogen interactions that may allow for correlation of gene expression patterns with clinical outcomes. In the present study, deletion of the cryptococcal copper-dependent transcription factor 1 (Cuf1) led to defects in growth and virulence factor expression in low copper conditions. In mouse models, cuf1Delta strains exhibited reduced dissemination to the brain, but no change in lung growth, suggesting copper is limiting in neurologic infections. To examine this further, a biologic probe of available copper was constructed using the cryptococcal CUF1-dependent copper transporter, CTR4. Fungal cells demonstrated high CTR4 expression levels after phagocytosis by macrophage-like J774.16 cells and during infection of mouse brains, but not lungs, consistent with limited copper availability during neurologic infection. This was extended to human brain infections by demonstrating CTR4 expression during C. neoformans infection of an AIDS patient. Moreover, high CTR4 expression by cryptococcal strains from 24 solid organ transplant patients was associated with dissemination to the CNS. Our results suggest that copper acquisition plays a central role in fungal pathogenesis during neurologic infection and that measurement of stable traits such as CTR4 expression may be useful for risk stratification of individuals with cryptococcosis.
Waterman
Scott R
SR
Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.
Hacham
Moshe
M
Hu
Guowu
G
Zhu
Xudong
X
Park
Yoon-Dong
YD
Shin
Soowan
S
Panepinto
John
J
Valyi-Nagy
Tibor
T
Beam
Craig
C
Husain
Shahid
S
Singh
Nina
N
Williamson
Peter R
PR
D000328:Adult; D000818:Animals; D001921:Brain / Q000382:microbiology; D027682:Cation Transport Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D003300:Copper / Q000378:metabolism*; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008875:Middle Aged; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014774:Virulence
D027682:Cation Transport Proteins; D005656:Fungal Proteins; D014157:Transcription Factors; D003300:Copper