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Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens

Highly immunogenic exotoxins are used as carrier proteins because they efficiently improve the immunogenicity of polysaccharides. However, their efficiency with protein antigens remains unclear. In the current study, the candidate antigen PA0833 from Pseudomonas aeruginosa was fused to the α-hemolys...

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Autores principales: Zou, Jin-Tao, Jing, Hai-Ming, Yuan, Yue, Lei, Lang-Huan, Chen, Zhi-Fu, Gou, Qiang, Xiong, Qing-Shan, Zhang, Xiao-Li, Zhao, Zhuo, Zhang, Xiao-Kai, Zeng, Hao, Zou, Quan-Ming, Zhang, Jin-Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294524/
https://www.ncbi.nlm.nih.gov/pubmed/34288976
http://dx.doi.org/10.1371/journal.ppat.1009752
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author Zou, Jin-Tao
Jing, Hai-Ming
Yuan, Yue
Lei, Lang-Huan
Chen, Zhi-Fu
Gou, Qiang
Xiong, Qing-Shan
Zhang, Xiao-Li
Zhao, Zhuo
Zhang, Xiao-Kai
Zeng, Hao
Zou, Quan-Ming
Zhang, Jin-Yong
author_facet Zou, Jin-Tao
Jing, Hai-Ming
Yuan, Yue
Lei, Lang-Huan
Chen, Zhi-Fu
Gou, Qiang
Xiong, Qing-Shan
Zhang, Xiao-Li
Zhao, Zhuo
Zhang, Xiao-Kai
Zeng, Hao
Zou, Quan-Ming
Zhang, Jin-Yong
author_sort Zou, Jin-Tao
collection PubMed
description Highly immunogenic exotoxins are used as carrier proteins because they efficiently improve the immunogenicity of polysaccharides. However, their efficiency with protein antigens remains unclear. In the current study, the candidate antigen PA0833 from Pseudomonas aeruginosa was fused to the α-hemolysin mutant Hla(H35A) from Staphylococcus aureus to form a Hla(H35A)-PA0833 fusion protein (HPF). Immunization with HPF resulted in increased PA0833-specific antibody titers, higher protective efficacy, and decreased bacterial burden and pro-inflammatory cytokine secretion compared with PA0833 immunization alone. Using fluorescently labeled antigens to track antigen uptake and delivery, we found that Hla(H35A) fusion significantly improved antigen uptake in injected muscles and antigen delivery to draining lymph nodes. Both in vivo and in vitro studies demonstrated that the increased antigen uptake after immunization with HPF was mainly due to monocyte- and macrophage-dependent macropinocytosis, which was probably the result of HPF binding to ADAM10, the Hla host receptor. Furthermore, a transcriptome analysis showed that several immune signaling pathways were activated by HPF, shedding light on the mechanism whereby Hla(H35A) fusion improves immunogenicity. Finally, the improvement in immunogenicity by Hla(H35A) fusion was also confirmed with two other antigens, GlnH from Klebsiella pneumoniae and the model antigen OVA, indicating that Hla(H35A) could serve as a universal carrier protein to improve the immunogenicity of protein antigens.
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spelling pubmed-82945242021-07-31 Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens Zou, Jin-Tao Jing, Hai-Ming Yuan, Yue Lei, Lang-Huan Chen, Zhi-Fu Gou, Qiang Xiong, Qing-Shan Zhang, Xiao-Li Zhao, Zhuo Zhang, Xiao-Kai Zeng, Hao Zou, Quan-Ming Zhang, Jin-Yong PLoS Pathog Research Article Highly immunogenic exotoxins are used as carrier proteins because they efficiently improve the immunogenicity of polysaccharides. However, their efficiency with protein antigens remains unclear. In the current study, the candidate antigen PA0833 from Pseudomonas aeruginosa was fused to the α-hemolysin mutant Hla(H35A) from Staphylococcus aureus to form a Hla(H35A)-PA0833 fusion protein (HPF). Immunization with HPF resulted in increased PA0833-specific antibody titers, higher protective efficacy, and decreased bacterial burden and pro-inflammatory cytokine secretion compared with PA0833 immunization alone. Using fluorescently labeled antigens to track antigen uptake and delivery, we found that Hla(H35A) fusion significantly improved antigen uptake in injected muscles and antigen delivery to draining lymph nodes. Both in vivo and in vitro studies demonstrated that the increased antigen uptake after immunization with HPF was mainly due to monocyte- and macrophage-dependent macropinocytosis, which was probably the result of HPF binding to ADAM10, the Hla host receptor. Furthermore, a transcriptome analysis showed that several immune signaling pathways were activated by HPF, shedding light on the mechanism whereby Hla(H35A) fusion improves immunogenicity. Finally, the improvement in immunogenicity by Hla(H35A) fusion was also confirmed with two other antigens, GlnH from Klebsiella pneumoniae and the model antigen OVA, indicating that Hla(H35A) could serve as a universal carrier protein to improve the immunogenicity of protein antigens. Public Library of Science 2021-07-21 /pmc/articles/PMC8294524/ /pubmed/34288976 http://dx.doi.org/10.1371/journal.ppat.1009752 Text en © 2021 Zou et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Zou, Jin-Tao
Jing, Hai-Ming
Yuan, Yue
Lei, Lang-Huan
Chen, Zhi-Fu
Gou, Qiang
Xiong, Qing-Shan
Zhang, Xiao-Li
Zhao, Zhuo
Zhang, Xiao-Kai
Zeng, Hao
Zou, Quan-Ming
Zhang, Jin-Yong
Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title_full Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title_fullStr Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title_full_unstemmed Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title_short Pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
title_sort pore-forming alpha-hemolysin efficiently improves the immunogenicity and protective efficacy of protein antigens
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294524/
https://www.ncbi.nlm.nih.gov/pubmed/34288976
http://dx.doi.org/10.1371/journal.ppat.1009752
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