{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:35:16Z","timestamp":1775889316632,"version":"3.50.1"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2012,10,2]],"date-time":"2012-10-02T00:00:00Z","timestamp":1349136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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 homeostasis in the virulence of\n            <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n            based on a role for a\n            <jats:italic>CUF1<\/jats:italic>\n            copper regulatory factor in mouse models and in a human patient cohort.\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            mutant lacking the\n            <jats:italic>CUF1<\/jats:italic>\n            -dependent copper transporter,\n            <jats:italic>CTR4<\/jats:italic>\n            , grows normally in rich medium at 37\u00b0C 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\n            <jats:italic>CTR4<\/jats:italic>\n            -fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by\n            <jats:italic>ex vivo<\/jats:italic>\n            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\n            <jats:italic>CTR4<\/jats:italic>\n            in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for\n            <jats:italic>CTR4<\/jats:italic>\n            in copper-related homeostasis and subsequently in fungal virulence.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            <jats:italic>Crytococcus neoformans<\/jats:italic>\n            is a significant global fungal pathogen, and copper homeostasis is a relatively unexplored aspect of microbial pathogenesis that could lead to novel therapeutics. Previous studies correlated expression levels of a Ctr4 copper transporter to development of meningoencephalitis in a patient cohort of solid-organ transplants, but a direct role for Ctr4 in mammalian pathogenesis has not been demonstrated. The present studies utilize a \u0394\n            <jats:italic>ctr4<\/jats:italic>\n            mutant strain which revealed an important role for\n            <jats:italic>CTR4<\/jats:italic>\n            in\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            infections in mice and relate the gene product to homeostatic control of copper and growth under nutrient-restricted conditions. Robust expression levels of\n            <jats:italic>CTR4<\/jats:italic>\n            during fungal infection were exploited to demonstrate expression and lung cryptococcal disease using\n            <jats:italic>ex vivo<\/jats:italic>\n            fluorescence imaging. In summary, these studies are the first to directly demonstrate a role for a copper transporter in fungal disease and provide an\n            <jats:italic>ex vivo<\/jats:italic>\n            imaging tool for further study of cryptococcal gene expression and pathogenesis.\n          <\/jats:p>","DOI":"10.1128\/mbio.00285-12","type":"journal-article","created":{"date-parts":[[2012,10,3]],"date-time":"2012-10-03T01:40:07Z","timestamp":1349228407000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":54,"title":["Role of\n            <i>CTR4<\/i>\n            in the Virulence of Cryptococcus neoformans"],"prefix":"10.1128","volume":"3","author":[{"given":"Scott R.","family":"Waterman","sequence":"first","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA"},{"name":"Laboratory of Clinical Infectious Diseases, National 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