{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:37:56Z","timestamp":1790797076480,"version":"4.1.0"},"reference-count":75,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2013,7,2]],"date-time":"2013-07-02T00:00:00Z","timestamp":1372723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,8,30]],"date-time":"2013-08-30T00:00:00Z","timestamp":1377820800000},"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":[[2013,8,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Bruton\u2019s tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance to<jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>infection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6\u00a0weeks after infection with<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>strain 52D (CN52D); however, consistent with the propensity for greater virulence of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>strain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3\u00a0weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total and<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellular<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>cells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6\u00a0weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancing<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>phagocytosis and restricting<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>enlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>is a fungal pathogen that causes an estimated 600,000 deaths per year. Most infections occur in individuals who are immunocompromised, with the majority of cases occurring in those with HIV\/AIDS, but healthy individuals also develop disease. Immunoglobulin M (IgM) has been linked to resistance to disease in humans and mice. In this article, we found that X-linked immunodeficient (XID) mice, which have markedly reduced levels of IgM, were unable to contain<jats:italic>Cryptococcus<\/jats:italic>in the lungs. This was associated with reduced yeast uptake by macrophages, an aberrant tissue inflammatory response, an enlargement of the yeast cells in the lungs, and fungal dissemination to the brain. Since XID mice have a mutation in the Bruton\u2019s tyrosine kinase (Btk) gene, our data suggest that treatments aimed at blocking the function of Btk could pose a higher risk for cryptococcosis.<\/jats:p>","DOI":"10.1128\/mbio.00265-13","type":"journal-article","created":{"date-parts":[[2013,7,3]],"date-time":"2013-07-03T04:39:14Z","timestamp":1372826354000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":79,"title":["X-Linked Immunodeficient Mice Exhibit Enhanced Susceptibility to Cryptococcus neoformans Infection"],"prefix":"10.1128","volume":"4","author":[{"given":"Wendy A.","family":"Szymczak","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan, USA"},{"name":"VA Ann Arbor Health System, Research Service, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven K.","family":"Lundy","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Dufaud","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan, USA"},{"name":"VA Ann Arbor Health System, Research Service, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liise-anne","family":"Pirofski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38322"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.6.3674-3679.2004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.7.3419"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.4049\/jimmunol.131.3.1455","article-title":"Antibody-dependent leukocyte killing of Cryptococcus neoformans","volume":"131","author":"Miller GP","year":"1983","unstructured":"MillerGP KohlS . 1983. Antibody-dependent leukocyte killing of Cryptococcus neoformans. J. Immunol. 131:1455\u20131459.","journal-title":"J. Immunol."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.3.1571-1580.2002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901638"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00278-07"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.60.10.4080-4087.1992"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.8.4810-4818.2004"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.3.2100"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/599318"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061041"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141890"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1005603"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.8.3320"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100034"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.9.4564"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.04.011"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813411106"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121631109"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0711372"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2901"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121632109"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121627109"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.7.3819"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201514"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/13.9.1193"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8332901"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90114-0"},{"key":"e_1_3_2_31_2","first-page":"180","article-title":"Rapid restoration of B-cell function in XID mice by intravenous transfer of peritoneal cavity B cells","volume":"83","author":"Prior L","year":"1994","unstructured":"PriorL PiersonS WoodlandRT RiggsJ . 1994. Rapid restoration of B-cell function in XID mice by intravenous transfer of peritoneal cavity B cells. Immunology 83:180\u2013183.","journal-title":"Immunology"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.136.4.931"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.47.1.282-287.1985"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2010.01.003"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903162"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.12.038"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017204"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00809-09"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.153.3.694"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.146.4.1138"},{"key":"e_1_3_2_41_2","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.4049\/jimmunol.128.5.2032","article-title":"Streptococcal group A carbohydrate has properties of both a thymus-independent (TI-2) and a thymus-dependent antigen","volume":"128","author":"Briles DE","year":"1982","unstructured":"BrilesDE NahmM MarionTN PerlmutterRM DavieJM . 1982. Streptococcal group A carbohydrate has properties of both a thymus-independent (TI-2) and a thymus-dependent antigen. J. Immunol. 128:2032\u20132035.","journal-title":"J. Immunol."},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1997.00270.x"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-005-1387-0"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.2.1027"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.04.025"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6346"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080598"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0207"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.6.2914"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2234"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2381"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031223"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.2.271"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxh180"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080979"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100783"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002836"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2008.48"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.11.7222"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902011"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006854"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-147-8-2355"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/am.25.2.309-312.1973"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.22.6.1068-1070.1985"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323848"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01186.x"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000945"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000953"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00121-12"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00507-12"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300057"},{"key":"e_1_3_2_72_2","first-page":"181","article-title":"Defective Fc-, CR1- and CR3-mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients","volume":"13","author":"Amoras AL","year":"2003","unstructured":"AmorasAL KaneganeH MiyawakiT VilelaMM . 2003. Defective Fc-, CR1- and CR3-mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients. J. Investig. Allergol. Clin. Immunol. 13:181\u2013188.","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.42.7906"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar3400"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-397919"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.10.3358.422k04_3358_3365"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00265-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00265-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T18:07:13Z","timestamp":1715623633000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00265-13"}},"subtitle":[],"editor":[{"given":"Anna","family":"Vecchiarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]},{"given":"Antonio","family":"Cassone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,8,30]]},"references-count":75,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2013,8,30]]}},"alternative-id":["10.1128\/mBio.00265-13"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00265-13","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,8,30]]},"assertion":[{"value":"2013-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-06-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-07-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00265-13"}}