Alpha hemolysin,a pore-forming toxin from Staphylococcus aureus,is a critical virulence factor for bacteria.Previous studies have demonstrated that the Hla mutant H35A(HlaH35A)serves as a potent carrier protein for su...Alpha hemolysin,a pore-forming toxin from Staphylococcus aureus,is a critical virulence factor for bacteria.Previous studies have demonstrated that the Hla mutant H35A(HlaH35A)serves as a potent carrier protein for subunit vaccines,yet its immunomodulatory mechanisms remain incompletely understood.Here,we demonstrate that the HlaH35A fusion enhances vaccine efficacy by targeting A Disintegrin and Metalloproteinase 10(ADAM10)on dendritic cells(DCs),thereby activating the ADAM10-Notch signaling axis.Using the candidate antigen PA0833 from Pseudomonas aeruginosa as a model,we show that the HlaH35A-PA0833 fusion protein(HPF)significantly augments antigen uptake,DC maturation,and Notch-dependent transcriptional programs,particularly in conventional DCs(cDCs).The HlaH35A fusion drives the differentiation of Notch2-dependent cDC2s,which is marked by ESAM expression and IL-23 secretion.This process promotes Th17 and T follicular helper(Tfh)cell responses in draining lymph nodes,leading to elevated antigen-specific IgG1 titers and robust protection against acute Pseudomonas aeruginosa lung infection.Notably,ADAM10 or Notch inhibition abrogates these effects.Similarly,human monocyte-derived DCs exhibit enhanced maturation and Notch activation via the HlaH35A-ADAM 10 interaction.Our findings reveal that HlaH35A is a novel carrier protein that shapes adaptive immunity by modulating cDC2 differentiation via ADAM10-Notch2 signaling,suggesting a promising strategy for Th17/Tfh-oriented vaccine design.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.32170938 and No.32300778)the National Key Research and Development Program of China(2024YFC2310800)the Technological Innovation and Application Development Foundation of Chongqing(CSTB2024TIAD-STX0043).
文摘Alpha hemolysin,a pore-forming toxin from Staphylococcus aureus,is a critical virulence factor for bacteria.Previous studies have demonstrated that the Hla mutant H35A(HlaH35A)serves as a potent carrier protein for subunit vaccines,yet its immunomodulatory mechanisms remain incompletely understood.Here,we demonstrate that the HlaH35A fusion enhances vaccine efficacy by targeting A Disintegrin and Metalloproteinase 10(ADAM10)on dendritic cells(DCs),thereby activating the ADAM10-Notch signaling axis.Using the candidate antigen PA0833 from Pseudomonas aeruginosa as a model,we show that the HlaH35A-PA0833 fusion protein(HPF)significantly augments antigen uptake,DC maturation,and Notch-dependent transcriptional programs,particularly in conventional DCs(cDCs).The HlaH35A fusion drives the differentiation of Notch2-dependent cDC2s,which is marked by ESAM expression and IL-23 secretion.This process promotes Th17 and T follicular helper(Tfh)cell responses in draining lymph nodes,leading to elevated antigen-specific IgG1 titers and robust protection against acute Pseudomonas aeruginosa lung infection.Notably,ADAM10 or Notch inhibition abrogates these effects.Similarly,human monocyte-derived DCs exhibit enhanced maturation and Notch activation via the HlaH35A-ADAM 10 interaction.Our findings reveal that HlaH35A is a novel carrier protein that shapes adaptive immunity by modulating cDC2 differentiation via ADAM10-Notch2 signaling,suggesting a promising strategy for Th17/Tfh-oriented vaccine design.
