Abstract
Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y. pestis LcrV (100–270 aa) and YopE (50–213 aa) proteins conferred complete passive and active protection against lethal Y. enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y. enterocolitica 8081. rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up-regulation of both Th1 (TNF-α, IFN-γ, IL-2, and IL-12) and Th2 (IL-4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y. enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens.
Highlights
The human pathogenic Yersinia species, Y. enterocolitica and Y. pseudotuberculosis are enteric pathogens, whereas Y. pestis is the causative agent of acute zoonotic disease plague (Brubaker, 1991; Bottone, 1997; Perry and Fetherston, 1997)
In silico structure prediction of truncated recombinant proteins rV and rE derived from LcrV (100–270 aa) and YopE (50–213 aa.), respectively, of Y. pestis and their fusion construct was performed by I-TASSER (Roy et al, 2010) implemented composite modeling approach which includes the identification of suitable templates, reassembly of fragment structure, building of atomic models and selection of the best model (Zhang, 2009)
The rVE Confers Cell-Mediated Immune Protection stereo chemical quality assessment of the refined protein models were performed by inspection of the Psi/Phi Ramachandran plot obtained from PROCHECK
Summary
The human pathogenic Yersinia species, Y. enterocolitica and Y. pseudotuberculosis are enteric pathogens, whereas Y. pestis is the causative agent of acute zoonotic disease plague (Brubaker, 1991; Bottone, 1997; Perry and Fetherston, 1997). The emerging antibiotic resistant Y. pestis strains raise recurring zoonosis concern in modern world endemic regions and their possible employment as a potential bio-warfare agent (Galimand et al, 1997; White et al, 2002; Williamson and Oyston, 2012; Lister et al, 2012). These factors highlight the need to develop protective subunit vaccines against Y. pestis infection
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