Abstract
Background Schistosomiasis japonica is a zoonotic parasitic disease and oral vaccine delivery system would be benefit for prevention of this disease. Although attenuated salmonella has been used as an antigen expression vector for oral vaccine development, the membrane-bound vacuoles in which bacteria reside hinders the presentation of expressed heterologous antigens to the major histocompatibility complex (MHC) molecules. The present work used an attenuated Salmonella typhimurium strain VNP20009 to secretory expression of Sj23LHDGST bivalent antigen from Schistosoma japonicum and tested the protective efficacy against S. japonicum infection in orally immunized mice.Methodology/Principal FindingsPromoters (nirB or pagC) were used to express the antigen (Sj23LHDGST) and the Salmonella type III or α-hemolysin secretion system was employed to secrete it. The immunoblotting analysis and fluorescent microscopy revealed that the antigen was effectively expressed and delivered to the cytosol of macrophages in vitro. Among recombinant vaccine strains, an engineered VNP20009 which expressed the antigen by nirB promoter and secreted it through type III secretion system (nirB-sopE1–104-Sj23LHD-GST) efficiently protected against S. japonicum infection in a mouse model. This strain elicited a predominantly IgG2a antibody response and a markedly increase in the production of IL-12 and IFN-γ. The flow cytometric analysis demonstrated that this strain caused T cell activation as evidenced by significantly increased expression of CD44 and CD69.Conclusion/SignificanceOral delivery of antigen by nirB-driven Salmonella typhimurium type III secretion system is a novel, safe, inexpensive, efficient and convenient approach for schistosome vaccine development.
Highlights
Schistosomiasis, a disease cause by intravascular trematodes from the schistosome species, is one of the world’s major public health problems [1]
We used an attenuated S. typhimurium strain VNP20009, whose safety has been demonstrated in phase I clinical trial, to express the bivalent Schistosoma japonicum antigen Sj23LHD-glutathione S-transferase (GST) by an intracellular activated promoter and deliver it to host cells through type III secretion system
For rational design of an effective vaccine strain, we constructed plasmid vectors expressing chimeric proteins of sopE1–104, Nterminal 1–104 amino acids of sopE which are recognized as the secretion signal for type III secretion system, fused to S. japonicum antigen Sj23LHD-GST driven by the nitrite reductase B (nirB) or phoP activated gene C (pagC) promoter (Fig. 1A). nirB is activated by anaerobic conditions and pagC is inhibited by high magnesium concentration, these two promoters are both highly active in intracellular environment of professional antigen presenting cells [23]
Summary
Schistosomiasis, a disease cause by intravascular trematodes from the schistosome species, is one of the world’s major public health problems [1]. Five schistosome species infect humans including Schistosoma (S.) japonicum, S. mansoni, S. mekongi, S. intercalatum, and S. haematobium. Despite that numerous strategies have been devised and chemotherapeutic drugs such as praziquantel have been developed to combat this infectious disease, schistosomiasis still defies effective control [3]. Attenuated salmonella has been used as an antigen expression vector for oral vaccine development, the membrane-bound vacuoles in which bacteria reside hinders the presentation of expressed heterologous antigens to the major histocompatibility complex (MHC) molecules. The present work used an attenuated Salmonella typhimurium strain VNP20009 to secretory expression of Sj23LHDGST bivalent antigen from Schistosoma japonicum and tested the protective efficacy against S. japonicum infection in orally immunized mice
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