In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-21), p. e1009752-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009752
DOI:
10.1371/journal.ppat.1009752.g001
DOI:
10.1371/journal.ppat.1009752.g002
DOI:
10.1371/journal.ppat.1009752.g003
DOI:
10.1371/journal.ppat.1009752.g004
DOI:
10.1371/journal.ppat.1009752.g005
DOI:
10.1371/journal.ppat.1009752.g006
DOI:
10.1371/journal.ppat.1009752.g007
DOI:
10.1371/journal.ppat.1009752.s001
DOI:
10.1371/journal.ppat.1009752.s002
DOI:
10.1371/journal.ppat.1009752.s003
DOI:
10.1371/journal.ppat.1009752.s004
DOI:
10.1371/journal.ppat.1009752.s005
DOI:
10.1371/journal.ppat.1009752.s006
DOI:
10.1371/journal.ppat.1009752.s007
DOI:
10.1371/journal.ppat.1009752.s008
DOI:
10.1371/journal.ppat.1009752.s009
DOI:
10.1371/journal.ppat.1009752.s010
DOI:
10.1371/journal.ppat.1009752.r001
DOI:
10.1371/journal.ppat.1009752.r002
DOI:
10.1371/journal.ppat.1009752.r003
DOI:
10.1371/journal.ppat.1009752.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
Permalink