{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:06:17Z","timestamp":1792026377945,"version":"4.4.0"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI125045"],"award-info":[{"award-number":["R01 AI125045"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["RO1 AI172154"],"award-info":[{"award-number":["RO1 AI172154"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["75N93019C00064"],"award-info":[{"award-number":["75N93019C00064"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32 AI095213"],"award-info":[{"award-number":["T32 AI095213"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,8,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The global burden of infections due to the pathogenic fungus\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                      is substantial in persons with low CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell counts. Previously, we deleted three chitin deacetylase genes from\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      to create a chitosan-deficient, avirulent strain, designated as\n                      <jats:italic toggle=\"yes\">cda1\u22062\u22063\u2206<\/jats:italic>\n                      , which, when used as a vaccine, protected mice from challenge with virulent\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In contrast, protection was lost in mice lacking \u03b1\/\u03b2 T cells or CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Moreover, CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-\u03b3 (IFN\u03b3), tumor necrosis factor alpha (TNF\u03b1), or interleukin (IL)-23p19. A robust influx of leukocytes and IFN\u03b3- and TNF\u03b1-expressing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFN\u03b3 production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells are dispensable, IFN\u03b3 and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells have overlapping roles in generating protective immunity prior to\n                      <jats:italic toggle=\"yes\">cda1\u22062\u22063\u2206<\/jats:italic>\n                      vaccination. However, once vaccinated, protection becomes less dependent on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, suggesting a strategy for vaccinating HIV\n                      <jats:sup>+<\/jats:sup>\n                      persons prior to loss of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The fungus\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      is responsible for &gt;100,000 deaths annually, mostly in persons with impaired CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      , designated as\n                      <jats:italic toggle=\"yes\">cda1\u22062\u22063\u2206<\/jats:italic>\n                      . When used as a vaccine,\n                      <jats:italic toggle=\"yes\">cda1\u22062\u22063\u2206<\/jats:italic>\n                      protects mice against a subsequent challenge with a virulent\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were dispensible, protection was lost in mice genetically deficient in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and the cytokines IFN\u03b3, TNF\u03b1, or IL-23. A robust influx of cytokine-producing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01746-24","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T09:00:39Z","timestamp":1720515639000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Immunological correlates of protection mediated by a whole organism,\n                    <i>Cryptococcus neoformans<\/i>\n                    , vaccine deficient in chitosan"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-3112","authenticated-orcid":false,"given":"Charles A.","family":"Specht","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-4582","authenticated-orcid":false,"given":"Ruiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-0076","authenticated-orcid":false,"given":"Lorena V. N.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen M.","family":"Hester","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongming","family":"Mou","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5268-0646","authenticated-orcid":false,"given":"Diana","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrono K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-3020","authenticated-orcid":false,"given":"Camaron R.","family":"Hole","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woei C.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-2518","authenticated-orcid":false,"given":"Rajendra","family":"Upadhya","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lodge","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3799-3064","authenticated-orcid":true,"given":"Stuart M.","family":"Levitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00692-8"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00499-6"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/592690"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000850"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002205"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-021-00294-8"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02145-19"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02909-18"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01433-15"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00547-16"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b19-00841"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00274-06"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01359"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00198-23"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.10.051"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01872-17"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00399-06"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05138-11"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1356651"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6477"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/5.6.647"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/356154a0"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep23669"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/360225a0"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.13.6070"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00799-19"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01540"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200106)31:6<1944::aid-immu1944>3.0.co;2-r"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im0401s113"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.154.12.6644"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-023-00606-0"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.2.1098"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.157.10.4529"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0928-8244(95)00093-3"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.3.1788-1796.2005"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.005"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1515\/bmc-2018-0007"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053318"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030109"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.4.793"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.62.1.194-202.1994"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.152.8.3970"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30243-8"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.160.5.2393"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofy122"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa356"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.739027"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf1198"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit271"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2483"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1996.d01-870.x"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2274"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.5.2827"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1191782"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-018-0486-y"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2013.12.005"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00746-9"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-022-00570-3"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84624-9"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/350423a0"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.159.11.5682"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8456300"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8456301"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.4.1397"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.9.4831-4841.2003"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3722-7_27"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.3389\/ffunb.2023.1183291"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01746-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01746-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:37:16Z","timestamp":1791553036000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.01746-24"}},"subtitle":[],"editor":[{"given":"Kirsten","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,8,14]]},"references-count":68,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8,14]]}},"alternative-id":["10.1128\/mbio.01746-24"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01746-24","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,14]]},"assertion":[{"value":"2024-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01746-24"}}