Leishmania-Specific Promiscuous Membrane Protein Tubulin Folding Cofactor D Divulges Th1/Th2 Polarization in the Host via ERK - 1/2 and p38 MAPK Signaling Cascade

Abstract

Visceral leishmaniasis (VL)-related mortality and morbidity imposes a great deal of health concern across the globe. The existing anti-leishmanial drug regimen generally fails to eliminate newly emerging resistant isolates of this dreadful parasite. In such circumstances, the development of a prophylactic strategy to impart protection against the disease is likely to take center stage. In order to develop a promising prophylactic vaccine, it is desirable to identify an adequately potential vaccine candidate. In silico analysis of Leishmania tubulin folding cofactor D protein predicted its potential to activate both B- and T-cell repertoires. Furthermore, the ELISA employing anti-peptide₂₇ (a segment of tubulin folding cofactor D) antibody revealed its proficiency in VL diagnosis and treatment monitoring. The peptide₂₇ and its cocktail with another Leishmania peptide (peptide₂₃) prompted the up-regulation of pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-2, IL-17, etc., and the down-regulation of immune-regulatory cytokines, such as IL-10, in the immunized BALB/c mice. Coherent to the consequence of peptide-specific humoral immune response, peptide cocktail-based immunization ensued in the predominant amplification of pathogen-specific IgG2a over the IgG1 isotype, up-regulated proliferation of T lymphocytes, and enhanced production of nitric oxide, reactive oxygen species, etc. We also established that the peptide cocktail modulated host MAPK signaling to favor the amplification of Th₁-dominated immune response in the host. The peptide cocktail mediated the activation of the host immune armory, which was eventually translated into a significant decline in parasitic load in the visceral organs of experimental animals challenged with Leishmania donovani.

Keywords: Leishmania donovani; MAPK signaling; T-cell proliferation; Th1 response; humoral response; immunoprophylaxis; peptide cocktail; tubulin folding cofactor D.