| First Author | Specht CA | Year | 2024 |
| Journal | mBio | Volume | 15 |
| Issue | 8 | Pages | e0174624 |
| PubMed ID | 38980038 | Mgi Jnum | J:353853 |
| Mgi Id | MGI:7714176 | Doi | 10.1128/mbio.01746-24 |
| Citation | Specht CA, et al. (2024) Immunological correlates of protection mediated by a whole organism, Cryptococcus neoformans, vaccine deficient in chitosan. mBio 15(8):e0174624 |
| abstractText | 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 cda123, 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 alpha/beta 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-gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNgamma- and TNFalpha-expressing CD4(+) T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNgamma 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, IFNgamma and CD4(+) T cells have overlapping roles in generating protective immunity prior to cda123 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 >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 cda123. When used as a vaccine, cda123 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 IFNgamma, TNFalpha, 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. |
