{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:18:09Z","timestamp":1791418689385,"version":"4.3.3"},"reference-count":50,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2001,12,21]],"date-time":"2001-12-21T00:00:00Z","timestamp":1008892800000},"content-version":"vor","delay-in-days":234,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2001,5]]},"abstract":"<jats:p>The polysaccharide capsule surrounding <jats:italic>Cryptococcus neoformans<\/jats:italic> comprises manose, xylose and glucuronic acid, of which mannose is the major constituent. The GDP\u2010mannose biosynthesis pathway is highly conserved in fungi and consists of three key enzymes: phosphomannose isomerase (PMI), phosphomannomutase (PMM) and GDP\u2010mannose pyrophosphorylase (GMP). The <jats:italic>MAN1<\/jats:italic> gene, encoding for\u00a0the PMI enzyme, was isolated and sequenced from\u00a0<jats:italic>C. neoformans<\/jats:italic>, and a disruption of the <jats:italic>MAN1<\/jats:italic> gene was generated. One <jats:italic>MAN1<\/jats:italic> disruption mutant, <jats:italic>man1<\/jats:italic>, which showed poor capsule formation, reduced polysaccharide secretion and morphological abnormalities, was chosen for virulence studies. In both the rabbit and the mouse models of invasive cryptococcosis, <jats:italic>man1<\/jats:italic> was shown to be severely impaired in its virulence, with complete elimination of the yeast from the host. A reconstituted strain of <jats:italic>man1<\/jats:italic> was constructed using gene replacement at the native locus. The wild\u2010type and reconstituted strains were significantly more virulent than the knock\u2010out mutant in both animal models. Our findings reveal that PMI activity is essential for the survival of <jats:italic>C.\u00a0neoformans<\/jats:italic> in the host. The fact that the <jats:italic>man1<\/jats:italic> mutant was not pathogenic suggests that blocking mannose synthesis could be fungicidal in the mammalian host and thus an excellent target for antifungal drug development.<\/jats:p>","DOI":"10.1046\/j.1365-2958.2001.02401.x","type":"journal-article","created":{"date-parts":[[2003,3,12]],"date-time":"2003-03-12T11:37:52Z","timestamp":1047469072000},"page":"610-620","source":"Crossref","is-referenced-by-count":86,"title":["Identification and characterization of the <i>Cryptococcus neoformans<\/i> phosphomannose isomerase\u2010encoding gene, <i>MAN1<\/i>, and its impact on pathogenicity"],"prefix":"10.1111","volume":"40","author":[{"given":"Elizabeth A.","family":"Wills","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian S.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Del Poeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Casadevall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Perfect","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2001,12,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.23.3206"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.01852.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(92)90209-C"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.7.4912"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.5.2230-2236.1998"},{"key":"e_1_2_6_7_1","doi-asserted-by":"crossref","first-page":"5636","DOI":"10.1128\/JB.181.18.5636-5643.1999","article-title":"Isolation, characterization and localization of a capsule\u2010associated gene, CAP10, of Cryptococcus neoformans","volume":"181","author":"Chang Y.C.","year":"1999","journal-title":"J Bacteriol"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.64.6.1977-1983.1996"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.5.871"},{"key":"e_1_2_6_10_1","first-page":"879","article-title":"Soluble polysaccharides of Cryptococcus neoformans","volume":"43","author":"Cherniak R.","year":"1988","journal-title":"Infect Immun"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.62.5.1507-1512.1994"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0161-5890(80)90096-6"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.63.5.1899-1905.1995"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(91)90406-2"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.2.443-448.2000"},{"key":"e_1_2_6_16_1","doi-asserted-by":"crossref","unstructured":"Cox G.M. McDade H.C. Chen S.C.A. Tucker S.C. Gottfredsson M. Wright L.C.et al.(2000b)Extracellular phospholipase activity is a virulence factor forCryptococcus neoformans.Mol Microbiol38:1\u201311.","DOI":"10.1046\/j.1365-2958.2001.02236.x"},{"key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1128\/jb.161.1.249-257.1985","article-title":"Cloning of Escherichia coli and Pseudomonas aeruginosa phosphomannose isomerase genes and their expression in alginate\u2010negative mutants of Pseudomonas aeruginosa","volume":"161","author":"Darzins A.","year":"1985","journal-title":"J Bacteriol"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.16.1.129-135.1977"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002530051629"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1996.0648r.x"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00636177"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(86)91056-9"},{"key":"e_1_2_6_23_1","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1128\/jb.167.2.611-615.1986","article-title":"Overproduction and assay of Pseudomonas aeruginosa phosphomannose isomerase","volume":"167","author":"Gill J.F.","year":"1986","journal-title":"J Bacteriol"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112000"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(97)00122-2"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.8385"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.39.3.1214-1219.1983"},{"key":"e_1_2_6_28_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1128\/iai.3.2.287-294.1971","article-title":"Nonencapsulated variant of Cryptococcus neoformans 1. Virulence studies and characterization of soluble polysaccharide","volume":"3","author":"Kozel T.R.","year":"1971","journal-title":"Infect Immun"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/10.Supplement_2.S436"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/714030997"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-215-44121"},{"key":"e_1_2_6_32_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1128\/jb.107.3.759-769.1971","article-title":"Glucose and fructose metabolism in a phosphoglucoisomeraseless mutant of Saccharomyces cerevisiae","volume":"107","author":"Maitra P.K.","year":"1971","journal-title":"J Bacteriol"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(84)90030-1"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(90)90248-P"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.10.2576"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.173.6.2006-2010.1991"},{"key":"e_1_2_6_37_1","first-page":"177","article-title":"Chronic cryptococcal meningitis: a new experimental model in rabbits","volume":"62","author":"Perfect J.R.","year":"1980","journal-title":"Am J Pathol"},{"key":"e_1_2_6_38_1","doi-asserted-by":"crossref","first-page":"4446","DOI":"10.1128\/iai.61.10.4446-4451.1993","article-title":"The gene encoding phosphoribosylaminidazole carboxylase (ADE2) is essential for growth of Cryptococcus neoformans in cerebrospinal fluid","volume":"61","author":"Perfect J.R.","year":"1993","journal-title":"Infect Immun"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1099\/13500872-142-6-1557"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2000.01583.x"},{"key":"e_1_2_6_41_1","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J.","year":"1989"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.9.6030"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.12.7.2924"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/yea.320110402"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1006\/fgbi.1999.1126"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(87)90006-2"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/02681219780001351"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.5.1405-1411.1993"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-109-1-155"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/167.1.186"},{"key":"e_1_2_6_51_1","volume-title":"Harrison's Principles of Internal Medicine","author":"Wilson J.D.","year":"1991"}],"container-title":["Molecular Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2958.2001.02401.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1046\/j.1365-2958.2001.02401.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T22:31:32Z","timestamp":1697495492000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1046\/j.1365-2958.2001.02401.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,5]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2001,5]]}},"alternative-id":["10.1046\/j.1365-2958.2001.02401.x"],"URL":"https:\/\/doi.org\/10.1046\/j.1365-2958.2001.02401.x","archive":["Portico"],"relation":{},"ISSN":["0950-382X","1365-2958"],"issn-type":[{"value":"0950-382X","type":"print"},{"value":"1365-2958","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,5]]}}}