Role of CTR4 in the virulence of cryptococcus neoformans

Scott R. Waterman, y. D. Park, Meera Raja, Jin Qiu, Dima A. Hammoud, Thomas V. O'Halloran, Peter R. Williamson

Research output: Contribution to journalArticle

Abstract

While research has identified an important contribution for metals, such as iron, in microbial pathogenesis, the roles of other transition metals, such as copper, remain mostly unknown. Recent evidence points to a requirement for copper homeo-stasis in the virulence of Cryptococcus neoformans based on a role for a CUF1 copper regulatory factor in mouse models and in a human patient cohort. C. neoformans is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a C. neoformans mutant lacking the CUF1-dependent copper transporter, CTR4, grows normally in rich medium at 37°C but has reduced survival in macrophages and attenuated virulence in a mouse model. This reduced survival and virulence were traced to a growth defect under nutrient-restricted conditions. Expression studies using a full-length CTR4-fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by ex vivo fluorescent imaging. Inductively coupled mass spectroscopy (ICP-MS) was used to probe the copper quota of fungal cells grown in defined medium and recovered from brain, which suggested a role for a copper-protective function of CTR4 in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for CTR4 in copper-related homeostasis and subsequently in fungal virulence.

Original languageEnglish (US)
JournalmBio
Volume3
Issue number5
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Cryptococcus neoformans
Virulence
Copper
Metals
Macrophages
Survival
Metallothionein
Brain
Mass Spectrometry
Acquired Immunodeficiency Syndrome
Homeostasis
Iron
Food
Lung
Growth
Research

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Waterman, S. R., Park, Y. D., Raja, M., Qiu, J., Hammoud, D. A., O'Halloran, T. V., & Williamson, P. R. (2012). Role of CTR4 in the virulence of cryptococcus neoformans. mBio, 3(5). https://doi.org/10.1128/mBio.00285-12

Role of CTR4 in the virulence of cryptococcus neoformans. / Waterman, Scott R.; Park, y. D.; Raja, Meera; Qiu, Jin; Hammoud, Dima A.; O'Halloran, Thomas V.; Williamson, Peter R.

In: mBio, Vol. 3, No. 5, 2012.

Research output: Contribution to journalArticle

Waterman, SR, Park, YD, Raja, M, Qiu, J, Hammoud, DA, O'Halloran, TV & Williamson, PR 2012, 'Role of CTR4 in the virulence of cryptococcus neoformans', mBio, vol. 3, no. 5. https://doi.org/10.1128/mBio.00285-12
Waterman SR, Park YD, Raja M, Qiu J, Hammoud DA, O'Halloran TV et al. Role of CTR4 in the virulence of cryptococcus neoformans. mBio. 2012;3(5). https://doi.org/10.1128/mBio.00285-12
Waterman, Scott R. ; Park, y. D. ; Raja, Meera ; Qiu, Jin ; Hammoud, Dima A. ; O'Halloran, Thomas V. ; Williamson, Peter R. / Role of CTR4 in the virulence of cryptococcus neoformans. In: mBio. 2012 ; Vol. 3, No. 5.
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