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The fungal cell wall is an essential organelle which undergoes constant modification during various stages of growth and is critical for fungal pathogenesis. One critical component of the fungal cell wall is chitin, which in<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>is predominantly deacetylated to chitosan. We previously reported that three chitin deacetylase (CDA) genes have to be deleted to generate a chitosan-deficient<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>strain. This<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>strain was avirulent in mice, as it was rapidly cleared from the lungs of infected mice. Here, we report that clearance of the<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>strain was associated with sharply spiked concentrations of proinflammatory molecules that are known to be critical mediators of the orchestration of a protective Th1-type adaptive immune response. This was followed by the selective enrichment of the Th1-type T cell population in the<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>strain-infected mouse lung. Importantly, this response resulted in the development of robust protective immunity to a subsequent lethal challenge with a virulent wild-type<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>strain. Moreover, protective immunity was also induced in mice vaccinated with heat-killed<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>cells and was effective in multiple mouse strains. The results presented here provide a strong framework to develop the<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>strain as a potential vaccine candidate for<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>infection.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The most commonly used anticryptococcal therapies include amphotericin B, 5-fluorocytosine, and fluconazole alone or in combination. Major drawbacks of these treatment options are their limited efficacy, poor availability in limited resource areas, and potential toxicity. The development of antifungal vaccines and immune-based therapeutic interventions is promising and an attractive alternative to chemotherapeutics. Currently, there are no fungal vaccines in clinical use. This is the first report of a<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>deletion strain with an avirulent phenotype in mice exhibiting protective immunity when used as a vaccine after heat inactivation, although other strains that overexpress fungal or murine proteins have recently been shown to induce a protective response. The data presented here demonstrate the potential for developing the avirulent<jats:italic>cda1\u03942\u03943\u0394<\/jats:italic>strain into a vaccine-based therapy to treat<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>infection.<\/jats:p>","DOI":"10.1128\/mbio.00547-16","type":"journal-article","created":{"date-parts":[[2016,5,11]],"date-time":"2016-05-11T02:22:35Z","timestamp":1462933355000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":123,"title":["Induction of Protective Immunity to Cryptococcal Infection in Mice by a Heat-Killed, Chitosan-Deficient Strain of Cryptococcus neoformans"],"prefix":"10.1128","volume":"7","author":[{"given":"Rajendra","family":"Upadhya","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woei C.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Maybruck","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Specht","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart M.","family":"Levitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lodge","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328322ffac"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000850"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2011.05.009"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12281-010-0018-6"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2014.12.001"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01299-15"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.10.93"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104653"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2522"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.23.3.644-651.1979"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.4.793"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1567-1364.2006.00073.x"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.12.7049-7060.2000"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.5.3410-3412.2001"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"6026","DOI":"10.4049\/jimmunol.160.12.6026","article-title":"The antibody response to fungal melanin in mice","volume":"160","author":"Nosanchuk JD","year":"1998","unstructured":"Nosanchuk JD, Rosas AL, Casadevall A. 1998. 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