{"doi":"10.1128/mbio.01746-24","title":"Immunological correlates of protection mediated by a whole organism, <i>Cryptococcus neoformans</i> , vaccine deficient in chitosan","abstract":"ABSTRACT The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4 + T-cell counts. Previously, we deleted three chitin deacetylase genes from Cryptococcus neoformans to create a chitosan-deficient, avirulent strain, designated as cda1∆2∆3∆ , which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8 + T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4 + T cells. Moreover, CD4 + T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4 + T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4 + T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-γ (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4 + T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8 + T cells are dispensable, IFNγ and CD4 + T cells have overlapping roles in generating protective immunity prior to cda1∆2∆3∆ vaccination. However, once vaccinated, protection becomes less dependent on CD4 + T cells, suggesting a strategy for vaccinating HIV + persons prior to loss of CD4 + T cells. IMPORTANCE The fungus Cryptococcus neoformans is responsible for &gt;100,000 deaths annually, mostly in persons with impaired CD4 + T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans , designated as cda1∆2∆3∆ . When used as a vaccine, cda1∆2∆3∆ protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8 + T cells were dispensible, protection was lost in mice genetically deficient in CD4 + T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4 + T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4 + T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4 + T-cell dysfunction.","journal":"mBio","year":2024,"id":431696,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":629947,"name":"Ruiying Wang","orcid":"0000-0002-3638-4582","position":1,"is_corresponding":false},{"id":629946,"name":"Lorena V. N. Oliveira","orcid":"0000-0002-1762-0076","position":2,"is_corresponding":false},{"id":811668,"name":"Maureen M. Hester","orcid":"0000-0002-2680-4854","position":3,"is_corresponding":false},{"id":998361,"name":"Cristina Gómez","orcid":"0000-0001-8518-0095","position":4,"is_corresponding":false},{"id":812066,"name":"Zhongming Mou","orcid":null,"position":5,"is_corresponding":false},{"id":1235946,"name":"D. E. Carlson","orcid":"0009-0009-5268-0646","position":6,"is_corresponding":false},{"id":612557,"name":"Chrono K. Lee","orcid":null,"position":7,"is_corresponding":false},{"id":442330,"name":"Camaron R. Hole","orcid":"0000-0002-9363-3020","position":8,"is_corresponding":false},{"id":611576,"name":"Woei C. Lam","orcid":null,"position":9,"is_corresponding":false},{"id":1038906,"name":"Rajendra Upadhya","orcid":"0000-0001-7613-2518","position":10,"is_corresponding":false},{"id":342998,"name":"Jennifer K. Lodge","orcid":"0000-0002-2526-1210","position":11,"is_corresponding":false},{"id":612062,"name":"Stuart M. Levitz","orcid":"0000-0002-3799-3064","position":12,"is_corresponding":false},{"id":612063,"name":"Charles A. Specht","orcid":"0000-0002-5749-3112","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:59:30.747263Z","pmid":"38980038","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}