{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:48:52Z","timestamp":1792075732206,"version":"4.4.0"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2011,6,7]],"date-time":"2011-06-07T00:00:00Z","timestamp":1307404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2011,7,1]],"date-time":"2011-07-01T00:00:00Z","timestamp":1309478400000},"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":[[2011,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p><jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>is an important fungal pathogen of immunocompromised individuals, with a close relative,<jats:named-content content-type=\"genus-species\">Cryptococcus gattii<\/jats:named-content>, emerging as a serious threat for the immunocompetent. During initial infection,<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>colonizes the airspaces of the lungs, resulting in pneumonia, and subsequently migrates to the central nervous system (CNS). We sought to understand fungal carbon utilization during colonization of these fundamentally different niches within the host, in particular the roles of gluconeogenesis and glycolysis. We created mutants at key points in the gluconeogenesis\/glycolysis metabolic pathways that are restricted for growth on lactate and glucose, respectively. A phosphoenolpyruvate carboxykinase mutant (the<jats:italic>pck1\u2206<\/jats:italic>mutant), blocked for entry of 2- and 3-carbon substrates into gluconeogenesis and attenuated for virulence in a murine inhalation model, showed wild-type (WT) persistence in a rabbit cerebrospinal fluid (CSF) model of cryptococcosis. Conversely, both the pyruvate kinase (<jats:italic>pyk1\u2206<\/jats:italic>) and the hexose kinase I and II (<jats:italic>hxk1\u2206\/hxk2\u2206<\/jats:italic>) mutants, which show impaired glucose utilization, exhibited severely attenuated virulence in the murine inhalation model of cryptococcosis and decreased persistence in the CNS in both the rabbit CSF and the murine inhalation models while displaying adequate persistence in the lungs of mice. These data suggest that glucose utilization is critical for virulence of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>and persistence of the yeast in the CNS.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>is an emerging fungal pathogen of humans and is responsible for approximately 625,000 deaths annually among those suffering from HIV infection\/AIDS. The ability of this fungus to persist in the host, coupled with its propensity to colonize the CNS, makes the understanding of nutrient acquisition in the host a primary concern. In this study, we report a requirement of glucose utilization for virulence of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>that is separate from its role in ATP production in the pathogen. Furthermore, we show that inhibition of glycolysis is a viable antifungal drug target, and impaired ATP production via the<jats:italic>PYK1<\/jats:italic>deletion may serve as a model for dormant\/chronic fungal infection in the host. Taken together, these results demonstrate the critical importance of understanding basic metabolic processes of the fungus in the context of host-pathogen interactions.<\/jats:p>","DOI":"10.1128\/mbio.00103-11","type":"journal-article","created":{"date-parts":[[2011,6,8]],"date-time":"2011-06-08T04:50:11Z","timestamp":1307508611000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":106,"title":["Cryptococcus neoformans Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host"],"prefix":"10.1128","volume":"2","author":[{"given":"Michael S.","family":"Price","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisol","family":"Betancourt-Quiroz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dena L.","family":"Toffaletti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haily","family":"Vora","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanggan","family":"Hu","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories, The University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Kronstad","sequence":"additional","affiliation":[{"name":"The Michael Smith Laboratories, The University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Perfect","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/9781555818241"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328322ffac"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04220"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.2.5.1036-1045.2003"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402981101"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5520(02)00036-3"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.7.2.231-236.1973"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.7.4225-4237.2000"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(01)02035-2"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.2.885-890.1999"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.09.032"},{"key":"e_1_3_2_13_2","first-page":"281","volume-title":"Molecular principles of fungal pathogenesis","author":"Perfect JR","year":"2006","unstructured":"PerfectJR . 2006. Cryptococcus neoformans: a sugar-coated killer, p. 281\u2013303. In HeitmanJ FillerSG EdwardsJE MitchellAP , Molecular principles of fungal pathogenesis. ASM Press, Washington, DC."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid0401.980109"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2006.07.001"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.03059.x"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00676.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.3.5.1076-1087.2004"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/35083594"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03478.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00551-10"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06374.x"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00214-06"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200523048"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.10.5684-5694.2002"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209597"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1975.tb03966.x"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2010.08.002"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(00)88980-5"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1996.tb02514.x"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2008.05.001"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209443200"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1992.tb16720.x"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj0990001"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05477.x"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.1.5.719-724.2002"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04178.x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03412.x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2007.05.002"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01416-06"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.29.2.633-641.1980"},{"key":"e_1_3_2_43_2","first-page":"177","article-title":"Chronic cryptococcal meningitis: a new experimental model in rabbits","volume":"101","author":"Perfect JR","year":"1980","unstructured":"PerfectJR LangSD DurackDT . 1980. Chronic cryptococcal meningitis: a new experimental model in rabbits. Am. J. Pathol. 101:177\u2013194.","journal-title":"Am. J. Pathol."},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00565-09"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00624-06"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2008.00117.x"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1234"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.27787-0"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1006\/fgbi.1997.0989"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1567-1364.2010.00609.x"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00271-09"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02173011"},{"key":"e_1_3_2_53_2","doi-asserted-by":"crossref","first-page":"672","DOI":"10.4049\/jimmunol.136.2.672","article-title":"Macrophage-mediated fungistasis in vitro: requirements for intracellular and extracellular cytotoxicity","volume":"136","author":"Granger DL","year":"1986","unstructured":"GrangerDL PerfectJR DurackDT . 1986. Macrophage-mediated fungistasis in vitro: requirements for intracellular and extracellular cytotoxicity. J. Immunol. 136:672\u2013680.","journal-title":"J. Immunol."},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.95.2.527"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109679"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.37.10.3204-3209.1999"},{"key":"e_1_3_2_57_2","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1158\/0008-5472.613.65.2","article-title":"Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia","volume":"65","author":"Xu RH","year":"2005","unstructured":"XuRH . 2005. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 65:613\u2013621.","journal-title":"Cancer Res."},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(91)94004-V"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.23.3206"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.1.6.509-514.1975"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00896-08"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-148-8-2607"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(75)80083-0"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.5.1405-1411.1993"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00145-06"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00132-8"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2002-3-7-research0034"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2008.17"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.2.443-448.2000"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.8.4922-4933.2005"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00103-11","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00103-11","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T07:36:25Z","timestamp":1686123385000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00103-11"}},"subtitle":[],"editor":[{"given":"Fran\u00e7oise","family":"Dromer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,7]]},"references-count":70,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011,7]]}},"alternative-id":["10.1128\/mBio.00103-11"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00103-11","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7]]},"assertion":[{"value":"2011-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-05-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-06-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00103-11"}}