Protection of Mice against Experimental Cryptococcosis by Synthesized Peptides Delivered in Glucan Particles

Specht, Charles A.; Homan, E. Jane; Lee, Chrono K.; Mou, Zhongming; Gomez, Christina L.; Hester, Maureen M.; Abraham, Ambily; Rus, Florentina; Ostroff, Gary R.; Levitz, Stuart M.

doi:10.1128/mbio.03367-21

Cited by 19 publications

(12 citation statements)

References 47 publications

(74 reference statements)

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“…(B) Serum from mice vaccinated with the indicated synthesized Cda2 peptide. See Specht et al., 2022 ( 12 ) and Figure S3 for the peptide sequences. The Western blots have been rotated and cropped to show the relevant portions but not spliced or digitally manipulated.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown peptides derived from Cda2 protect BALB/c mice when used in GP-based vaccines ( 12 ). To gain further insight into which regions of the proteins may be involved in cross-reactive antibody responses, we probed the serum from mice vaccinated with GP-Cda2-peptides against recombinant proteins from the Cda family.…”

Section: Resultsmentioning

confidence: 99%

“…Subunit vaccines obviate or mitigate these concerns. In an effort to develop subunit vaccines, we screened twenty-two recombinant cryptococcal protein antigens delivered in glucan particles (GPs) for the ability to protect mice against an otherwise lethal challenge with C. neoformans ( 10 – 12 ). These extracellular antigens were selected and tested for their previously demonstrated immunogenicity, their presence in protective alkaline extracts of C. neoformans ( 13 ), and/or their RNA transcript abundance in the cerebrospinal fluid of human patients ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…For the present studies, we sought to determine whether homology across a protein family enhances vaccine efficacy by promoting a cross-reactive immune response. Four of the previously screened antigens belong to the chitin deacetylase family of proteins; three of these four are protective in our vaccine model: Cda1, Cda2, and Cda3 protect mice against C. neoformans challenge, while Fpd1 [sometimes referred to as Cda4 ( 15 )] does not ( 10 – 12 ). Another protective antigen, Cpd1, belongs to a family of three carboxypeptidases (Cpd) with extensive sequence conservation ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Cross-reactivity between vaccine antigens from the chitin deacetylase protein family improves survival in a mouse model of cryptococcosis

et al. 2022

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Meningitis due to the fungal pathogen Cryptococcus neoformans is estimated to cause nearly 200,000 deaths annually, mostly in resource-limited regions. We previously identified cryptococcal protein antigens which, when delivered in glucan particles, afford vaccine-mediated protection against an otherwise lethal infection. Many of these proteins exhibit significant homology to other similar cryptococcal proteins leading us to hypothesize that protection may be augmented by immunologic cross-reactivity to multiple members of a protein family. To examine the significance of protein cross-reactivity in vaccination, we utilized strains of Cryptococcus that are genetically deficient in select antigens, yet are still lethal in mice. Vaccination with a protein without homologs (e.g., Mep1 and Lhc1) protected against challenge with wild-type Cryptococcus, but not against a deletion strain lacking that protein. Contrastingly, vaccination with a single chitin deacetylase (Cda) protein protected against the corresponding deletion strain, presumably due to host recognition of one or more other family members still expressed in this strain. Vaccination with a single Cda protein induced cross-reactive antibody and interferon-gamma (IFNγ) immune responses to other Cda protein family members. Paradoxically, we saw no evidence of cross-protection within the carboxypeptidase family of proteins. Factors such as in vivo protein expression and the degree of homology across the family could inform the extent to which vaccine-mediated immunity is amplified. Together, these data suggest a role for prioritizing protein families in fungal vaccine design: increasing the number of immune targets generated by a single antigen may improve efficacy while diminishing the risk of vaccine-resistant strains arising from gene mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cross-reactivity between vaccine antigens from the chitin deacetylase protein family improves survival in a mouse model of cryptococcosis

et al. 2022

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“…Notably, there was the development of memory T cells and enhanced secondary responses following the challenge. C. neoformans chitin deacetylase 2 peptide (Cda2-Pep1) delivered in glucan particle (GP)-based vaccination robustly protected the mice following the challenge, and the immunity was correlated with their MHC-II binding affinity ( 156 ). Similarly, multi-epitope vaccine/s may be useful in controlling cryptococcosis ( 157 ).…”

Section: Pathogen-specific Antifungal T Cellsmentioning

confidence: 99%

T cell responses to control fungal infection in an immunological memory lens

2022

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In recent years, fungal vaccine research emanated significant findings in the field of antifungal T-cell immunity. The generation of effector T cells is essential to combat many mucosal and systemic fungal infections. The development of antifungal memory T cells is integral for controlling or preventing fungal infections, and understanding the factors, regulators, and modifiers that dictate the generation of such T cells is necessary. Despite the deficiency in the clear understanding of antifungal memory T-cell longevity and attributes, in this review, we will compile some of the existing literature on antifungal T-cell immunity in the context of memory T-cell development against fungal infections.

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