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Transcriptional profiling of cryptococcal cells harvested from cell culture medium or from macrophages found differential expression of metabolic and other functions during fungal adaptation to the intracellular environment. We focused on the <jats:styled-content style=\"fixed-case\"><jats:italic>ACL1<\/jats:italic><\/jats:styled-content> gene for <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010citrate lyase, which converts citrate to acetyl\u2010<jats:styled-content style=\"fixed-case\">CoA<\/jats:styled-content>, because this gene showed elevated transcript levels in macrophages and because of the importance of acetyl\u2010<jats:styled-content style=\"fixed-case\">CoA<\/jats:styled-content> as a central metabolite. Mutants lacking <jats:styled-content style=\"fixed-case\"><jats:italic>ACL1<\/jats:italic><\/jats:styled-content> showed delayed growth on medium containing glucose, reduced cellular levels of acetyl\u2010<jats:styled-content style=\"fixed-case\">CoA<\/jats:styled-content>, defective production of virulence factors, increased susceptibility to the antifungal drug fluconazole and decreased survival within macrophages. Importantly, <jats:styled-content style=\"fixed-case\"><jats:italic>acl1<\/jats:italic><\/jats:styled-content> mutants were unable to cause disease in a murine inhalation model, a phenotype that was more extreme than other mutants with defects in acetyl\u2010<jats:styled-content style=\"fixed-case\">CoA<\/jats:styled-content> production (e.g. an acetyl\u2010<jats:styled-content style=\"fixed-case\">CoA<\/jats:styled-content> synthetase mutant). Loss of virulence is likely due to perturbation of critical physiological interconnections between virulence factor expression and metabolism in <jats:italic><jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>.\u2009neoformans<\/jats:italic>. Phylogenetic analysis and structural modelling of cryptococcal <jats:styled-content style=\"fixed-case\"><jats:roman>Acl1<\/jats:roman><\/jats:styled-content> identified three indels unique to fungal protein sequences; these differences may provide opportunities for the development of pathogen\u2010specific inhibitors.<\/jats:p>","DOI":"10.1111\/mmi.12065","type":"journal-article","created":{"date-parts":[[2012,10,19]],"date-time":"2012-10-19T04:31:21Z","timestamp":1350621081000},"page":"1404-1423","source":"Crossref","is-referenced-by-count":33,"title":["A defect in <scp>ATP<\/scp>\u2010citrate lyase links acetyl\u2010<scp>CoA<\/scp> production, virulence factor elaboration and virulence in <i><scp>C<\/scp>ryptococcus neoformans<\/i>"],"prefix":"10.1111","volume":"86","author":[{"given":"Emma J.","family":"Griffiths","sequence":"first","affiliation":[{"name":"The Michael Smith Laboratories Department of Microbiology and Immunology Faculty of Land and Food Systems University of British Columbia  Vancouver BC Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanggan","family":"Hu","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories Department of Microbiology and Immunology Faculty of Land and Food Systems University of British Columbia  Vancouver BC Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Fries","sequence":"additional","affiliation":[{"name":"Department of Medicine Albert Einstein College of Medicine  Bronx NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lissa","family":"Caza","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories Department of Microbiology and Immunology Faculty of Land and Food Systems University of British Columbia  Vancouver BC Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Wang","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories Department of Microbiology and Immunology Faculty of Land and Food Systems University of British Columbia  Vancouver BC Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Gsponer","sequence":"additional","affiliation":[{"name":"Centre for High\u2010Throughput Biology Department of Biochemistry &amp; Molecular Biology University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcellene A.","family":"Gates\u2010Hollingsworth","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Nevada School of Medicine  Reno NV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Kozel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Nevada School of Medicine  Reno NV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"De Repentigny","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Faculty of Medicine University of Montreal  Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Kronstad","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories Department of Microbiology and Immunology Faculty of Land and Food Systems University of British Columbia  Vancouver BC Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,11]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211214200"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.7.10.986"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20631"},{"key":"e_1_2_6_5_1","volume-title":"Performance Standards for Antimicrobial Susceptibility Testing. 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