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Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans
Scott R. Waterman, … , Nina Singh, Peter R. Williamson
Scott R. Waterman, … , Nina Singh, Peter R. Williamson
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):794-802. https://doi.org/10.1172/JCI30006.
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Research Article Microbiology

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

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Abstract

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, cuf1Δ 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.

Authors

Scott R. Waterman, Moshe Hacham, Guowu Hu, Xudong Zhu, Yoon-Dong Park, Soowan Shin, John Panepinto, Tibor Valyi-Nagy, Craig Beam, Shahid Husain, Nina Singh, Peter R. Williamson

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Figure 6

CTR4 expression varies among cryptococcal isolates, and high levels of expression confer greater ability to disseminate to the brain in human patients.

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CTR4 expression varies among cryptococcal isolates, and high levels of ...
(A) Twenty-four C. neoformans primary isolates were obtained from consecutive patients (or an H99 laboratory strain) as described in the Methods. Cells were induced by inoculation in asparagine salts, and RNA was obtained and subjected to Northern blot using a fragment of the indicated gene. Ribosomal RNA (rRNA) was visualized by ethidium bromide staining of gels. (B) Northern blots were conducted in duplicate, and CTR4/ACT1 ratios were calculated for the indicated strains by densitometry. (C) Plot of CTR4/ACT1 ratios according to infected organ. Horizontal lines indicate the mean value for each group. P = 0.04.

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