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dc.contributor.authorUpadhya, Rajendra
dc.contributor.authorLam, Woei C.
dc.contributor.authorMaybruck, Brian
dc.contributor.authorSpecht, Charles A.
dc.contributor.authorLevitz, Stuart M.
dc.contributor.authorLodge, Jennifer K
dc.date2022-08-11T08:09:45.000
dc.date.accessioned2022-08-23T16:42:09Z
dc.date.available2022-08-23T16:42:09Z
dc.date.issued2016-05-10
dc.date.submitted2016-08-16
dc.identifier.citation<p>MBio. 2016 May 10;7(3). pii: e00547-16. doi: 10.1128/mBio.00547-16. <a href="http://dx.doi.org/10.1128/mBio.00547-16">Link to article on publisher's site</a></p>
dc.identifier.issn2150-7511 (Electronic)
dc.identifier.doi10.1128/mBio.00547-16
dc.identifier.pmid27165801
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40034
dc.description.abstractCryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths. 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 C. neoformans is predominantly deacetylated to chitosan. We previously reported that three chitin deacetylase (CDA) genes have to be deleted to generate a chitosan-deficient C. neoformans strain. This cda1Delta2Delta3Delta strain was avirulent in mice, as it was rapidly cleared from the lungs of infected mice. Here, we report that clearance of the cda1Delta2Delta3Delta 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 cda1Delta2Delta3Delta 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 C. neoformans strain. Moreover, protective immunity was also induced in mice vaccinated with heat-killed cda1Delta2Delta3Delta cells and was effective in multiple mouse strains. The results presented here provide a strong framework to develop the cda1Delta2Delta3Delta strain as a potential vaccine candidate for C. neoformans infection. IMPORTANCE: 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 C. neoformans 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 cda1Delta2Delta3Delta strain into a vaccine-based therapy to treat C. neoformans infection.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27165801&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2016 Upadhya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBacterial Infections and Mycoses
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectImmunoprophylaxis and Therapy
dc.titleInduction of Protective Immunity to Cryptococcal Infection in Mice by a Heat-Killed, Chitosan-Deficient Strain of Cryptococcus neoformans
dc.typeJournal Article
dc.source.journaltitlemBio
dc.source.volume7
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3845&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2840
dc.identifier.contextkey8985370
refterms.dateFOA2022-08-23T16:42:10Z
html.description.abstract<p>Cryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths. 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 C. neoformans is predominantly deacetylated to chitosan. We previously reported that three chitin deacetylase (CDA) genes have to be deleted to generate a chitosan-deficient C. neoformans strain. This cda1Delta2Delta3Delta strain was avirulent in mice, as it was rapidly cleared from the lungs of infected mice. Here, we report that clearance of the cda1Delta2Delta3Delta 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 cda1Delta2Delta3Delta 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 C. neoformans strain. Moreover, protective immunity was also induced in mice vaccinated with heat-killed cda1Delta2Delta3Delta cells and was effective in multiple mouse strains. The results presented here provide a strong framework to develop the cda1Delta2Delta3Delta strain as a potential vaccine candidate for C. neoformans infection.</p> <p>IMPORTANCE: 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 C. neoformans 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 cda1Delta2Delta3Delta strain into a vaccine-based therapy to treat C. neoformans infection.</p>
dc.identifier.submissionpathoapubs/2840
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pagese00547-16


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Copyright © 2016 Upadhya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's license is described as Copyright © 2016 Upadhya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.