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dc.contributor.authorSpecht, Charles A.
dc.contributor.authorHoman, E. Jane
dc.contributor.authorLee, Chrono K.
dc.contributor.authorMou, Zhongming
dc.contributor.authorGomez, Christina L.
dc.contributor.authorHester, Maureen M
dc.contributor.authorAbraham, Ambily
dc.contributor.authorRus, Florentina
dc.contributor.authorOstroff, Gary R.
dc.contributor.authorLevitz, Stuart M.
dc.date2022-08-11T08:08:28.000
dc.date.accessioned2022-08-23T15:56:04Z
dc.date.available2022-08-23T15:56:04Z
dc.date.issued2021-11-13
dc.date.submitted2021-12-01
dc.identifier.citation<p>bioRxiv 2021.11.12.468465; doi: https://doi.org/10.1101/2021.11.12.468465. <a href="https://doi.org/10.1101/2021.11.12.468465" target="_blank" title="view preprint in biorxiv">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2021.11.12.468465
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29891
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>
dc.description.abstractThe high global burden of cryptococcosis has made development of a protective vaccine a public health priority. We previously demonstrated that a vaccine composed of recombinant Cryptococcus neoformans chitin deacetylase 2 (Cda2) delivered in glucan particles (GPs) protects BALB/c and C57BL/6 mice from an otherwise lethal challenge with a highly virulent C. neoformans strain. An immunoinformatic analysis of Cda2 revealed a peptide sequence predicted to have strong binding to the MHC Class II (MHC II) H2-IAd allele found in BALB/c mice. BALB/c mice vaccinated with GPs containing a 32 amino acid peptide (Cda2-Pep1) that included this strong binding region were protected from cryptococcosis. Protection was lost with GP-based vaccines containing versions of recombinant Cda2 protein and Cda2-Pep1 with mutations predicted to greatly diminish MHC II binding. Cda2 has homology to the three other C. neoformans chitin deacetylases, Cda1, Cda3 and Fpd1, in the high MHC II binding region. GPs loaded with homologous peptides of Cda1, Cda3 and Fpd1 protected BALB/c mice from experimental cryptococcosis, albeit not as robustly as the Cda2-Pep1 vaccine. Finally, seven other peptides were synthesized based on regions in Cda2 predicted to contain promising CD4+ T cell epitopes in BALB/c or C57BL/6 mice. While five peptide vaccines significantly protected BALB/c mice, only one protected C57BL/6 mice. Thus, GP-based vaccines containing a single peptide can protect mice against cryptococcosis. However, given the diversity of human MHC II alleles, a peptide-based Cryptococcus vaccine for use in humans would be challenging and likely need to contain multiple peptide sequences. Importance: Cryptococcosis, due to infection by fungi of the Cryptococcus neoformans species complex, is responsible for substantial morbidity and mortality in immunocompromised persons, particularly those with AIDS. Cryptococcal vaccines are a public health priority yet are not available for human use. We previously demonstrated mice could be protected from experimental cryptococcosis with vaccines composed of recombinant cryptococcal proteins encased in hollow highly purified yeast cell walls (glucan particles). Here, we examined one such protective protein, Cda2, and using bioinformatics, identified a region predicted to stimulate strong T cell responses. A peptide containing this region formulated in glucan particle-based vaccines protected mice as well as the recombinant protein. Other peptide vaccines also protected, including peptides containing sequences from proteins homologous to Cda2. These preclinical mouse studies provide a proof of principle that peptides can be effective as vaccines to protect against cryptococcosis and that bioinformatic approaches can guide peptide selection.
dc.language.isoen_US
dc.relationNow published in mBio doi: 10.1128/mbio.03367-21
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectImmunology
dc.subjectcryptococcosis
dc.subjectvaccine
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBacterial Infections and Mycoses
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectImmunology and Infectious Disease
dc.titleProtection of mice against experimental cryptococcosis by synthesized peptides delivered in glucan particles [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3121&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2097
dc.identifier.contextkey26415053
refterms.dateFOA2022-08-23T15:56:04Z
html.description.abstract<p><p id="x-x-p-3">The high global burden of cryptococcosis has made development of a protective vaccine a public health priority. We previously demonstrated that a vaccine composed of recombinant <em>Cryptococcus neoformans</em> chitin deacetylase 2 (Cda2) delivered in glucan particles (GPs) protects BALB/c and C57BL/6 mice from an otherwise lethal challenge with a highly virulent <em>C. neoformans</em> strain. An immunoinformatic analysis of Cda2 revealed a peptide sequence predicted to have strong binding to the MHC Class II (MHC II) H2-IAd allele found in BALB/c mice. BALB/c mice vaccinated with GPs containing a 32 amino acid peptide (Cda2-Pep1) that included this strong binding region were protected from cryptococcosis. Protection was lost with GP-based vaccines containing versions of recombinant Cda2 protein and Cda2-Pep1 with mutations predicted to greatly diminish MHC II binding. Cda2 has homology to the three other <em>C. neoformans</em> chitin deacetylases, Cda1, Cda3 and Fpd1, in the high MHC II binding region. GPs loaded with homologous peptides of Cda1, Cda3 and Fpd1 protected BALB/c mice from experimental cryptococcosis, albeit not as robustly as the Cda2-Pep1 vaccine. Finally, seven other peptides were synthesized based on regions in Cda2 predicted to contain promising CD4+ T cell epitopes in BALB/c or C57BL/6 mice. While five peptide vaccines significantly protected BALB/c mice, only one protected C57BL/6 mice. Thus, GP-based vaccines containing a single peptide can protect mice against cryptococcosis. However, given the diversity of human MHC II alleles, a peptide-based <em>Cryptococcus</em> vaccine for use in humans would be challenging and likely need to contain multiple peptide sequences. <p id="x-x-p-4">Importance: Cryptococcosis, due to infection by fungi of the <em>Cryptococcus neoformans</em> species complex, is responsible for substantial morbidity and mortality in immunocompromised persons, particularly those with AIDS. Cryptococcal vaccines are a public health priority yet are not available for human use. We previously demonstrated mice could be protected from experimental cryptococcosis with vaccines composed of recombinant cryptococcal proteins encased in hollow highly purified yeast cell walls (glucan particles). Here, we examined one such protective protein, Cda2, and using bioinformatics, identified a region predicted to stimulate strong T cell responses. A peptide containing this region formulated in glucan particle-based vaccines protected mice as well as the recombinant protein. Other peptide vaccines also protected, including peptides containing sequences from proteins homologous to Cda2. These preclinical mouse studies provide a proof of principle that peptides can be effective as vaccines to protect against cryptococcosis and that bioinformatic approaches can guide peptide selection.</p>
dc.identifier.submissionpathfaculty_pubs/2097
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentMedicine, Division of Infectious Diseases and Immunology


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.