Immune evasion by Cryptococcus gattii in vaccinated mice coinfected with C. neoformans

Hester, Maureen M.; Carlson, Diana; Lodge, Jennifer K.; Levitz, Stuart M.; Specht, Charles A.

doi:10.3389/fimmu.2024.1356651

Cited by 4 publications

(1 citation statement)

References 73 publications

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“…However, the A/J, BALB/c, CBA/J, and even DBA/J mouse strains can serve as a useful tool for identifying host factors that are absent or minimally elicited in C57BL/6J mice. 8 Publications [9][10][11]17,[134][135][136][137] 18 Publications [18][19][20]25,39,41,56,57,81,[138][139][140][141][142][143][144][145][146] A/J 0 Publications 0 Publications 3 Publications [39,56,57] BALB/c 9 Publications [69,71,72,[147][148][149][150][151][152] 1 Publication [153] 15 Publications [18,[39][40][41]56,138,142,143,[154][155]<...…”

Section: Recommendations For Inbred Mouse Strains Based On C Neoforma...mentioning

confidence: 99%

Inbred Mouse Models in Cryptococcus neoformans Research

Ding,

Nielsen

2024

JoF

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Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models.

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Section: Recommendations For Inbred Mouse Strains Based On C Neoforma...mentioning

confidence: 99%

Inbred Mouse Models in Cryptococcus neoformans Research

Ding,

Nielsen

2024

JoF

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Immunological correlates of protection mediated by a whole organismCryptococcus neoformansvaccine deficient in chitosan

Specht,

Wang,

Oliveira

et al. 2024

Preprint

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The global burden of infections due to the pathogenic fungusCryptococcusis substantial in persons with low CD4+T cell counts. Previously, we deleted three chitin deacetylase genes fromC. neoformansto create a chitosan-deficient, avirulent strain, designatedcda1Δ2Δ3Δwhich, when used as a vaccine, protected mice from challenge with virulentC. neoformansstrain 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 IFNγ, TNFα, or 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 tocda1Δ2Δ3Δvaccination. 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.ImportanceThe fungusCryptococcus neoformansis 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 ofC. neoformans, designatedcda1Δ2Δ3Δ. When used as a vaccine,cda1Δ2Δ3Δprotects mice against a subsequent challenge with a virulentC. neoformansstrain. 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 for future CD4+T cell dysfunction.

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Immunological correlates of protection mediated by a whole organism, Cryptococcus neoformans , vaccine deficient in chitosan

Specht,

Wang,

Oliveira

et al. 2024

mBio

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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 >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.

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Immune evasion by Cryptococcus gattii in vaccinated mice coinfected with C. neoformans

Cited by 4 publications

References 73 publications

Inbred Mouse Models in Cryptococcus neoformans Research

Inbred Mouse Models in Cryptococcus neoformans Research

Immunological correlates of protection mediated by a whole organismCryptococcus neoformansvaccine deficient in chitosan

Immunological correlates of protection mediated by a whole organism, Cryptococcus neoformans , vaccine deficient in chitosan

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