Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts

ABSTRACT A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunopro...

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Autores principales:	Charles A. Specht, Chrono K. Lee, Haibin Huang, Donald J. Tipper, Zu T. Shen, Jennifer K. Lodge, John Leszyk, Gary R. Ostroff, Stuart M. Levitz
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6faaf383d1ef450988f01a6770c12ae6
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spelling	oai:doaj.org-article:6faaf383d1ef450988f01a6770c12ae62021-11-15T15:41:22ZProtection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts10.1128/mBio.01905-152150-7511https://doaj.org/article/6faaf383d1ef450988f01a6770c12ae62015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01905-15https://doaj.org/toc/2150-7511ABSTRACT A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains of C. neoformans and C. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+ T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine. IMPORTANCE The encapsulated yeast Cryptococcus neoformans and its closely related sister species, Cryptococcus gattii, are major causes of morbidity and mortality, particularly in immunocompromised persons. This study reports on the preclinical development of vaccines to protect at-risk populations from cryptococcosis. Antigens were extracted from Cryptococcus by treatment with an alkaline solution. The extracted antigens were then packaged into glucan particles, which are hollow yeast cell walls composed mainly of β-glucans. The glucan particle-based vaccines elicited robust T cell immune responses and protected mice from otherwise-lethal challenge with virulent strains of C. neoformans and C. gattii. The technology used for antigen extraction and subsequent loading into the glucan particle delivery system is relatively simple and can be applied to vaccine development against other pathogens.Charles A. SpechtChrono K. LeeHaibin HuangDonald J. TipperZu T. ShenJennifer K. LodgeJohn LeszykGary R. OstroffStuart M. LevitzAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Charles A. Specht Chrono K. Lee Haibin Huang Donald J. Tipper Zu T. Shen Jennifer K. Lodge John Leszyk Gary R. Ostroff Stuart M. Levitz Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
description	ABSTRACT A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains of C. neoformans and C. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+ T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine. IMPORTANCE The encapsulated yeast Cryptococcus neoformans and its closely related sister species, Cryptococcus gattii, are major causes of morbidity and mortality, particularly in immunocompromised persons. This study reports on the preclinical development of vaccines to protect at-risk populations from cryptococcosis. Antigens were extracted from Cryptococcus by treatment with an alkaline solution. The extracted antigens were then packaged into glucan particles, which are hollow yeast cell walls composed mainly of β-glucans. The glucan particle-based vaccines elicited robust T cell immune responses and protected mice from otherwise-lethal challenge with virulent strains of C. neoformans and C. gattii. The technology used for antigen extraction and subsequent loading into the glucan particle delivery system is relatively simple and can be applied to vaccine development against other pathogens.
format	article
author	Charles A. Specht Chrono K. Lee Haibin Huang Donald J. Tipper Zu T. Shen Jennifer K. Lodge John Leszyk Gary R. Ostroff Stuart M. Levitz
author_facet	Charles A. Specht Chrono K. Lee Haibin Huang Donald J. Tipper Zu T. Shen Jennifer K. Lodge John Leszyk Gary R. Ostroff Stuart M. Levitz
author_sort	Charles A. Specht
title	Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
title_short	Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
title_full	Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
title_fullStr	Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
title_full_unstemmed	Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts
title_sort	protection against experimental cryptococcosis following vaccination with glucan particles containing <italic toggle="yes">cryptococcus</italic> alkaline extracts
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/6faaf383d1ef450988f01a6770c12ae6
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Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing <italic toggle="yes">Cryptococcus</italic> Alkaline Extracts

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