Abstract
Immunotherapy, a treatment based on host immune system activation, has been shown to provide a substitute for marginally effective conventional chemotherapy in controlling visceral leishmaniasis (VL), the deadliest form of leishmaniasis. As the majority of endemic inhabitants exhibit either subclinical or asymptomatic infection which often develops into the active disease state, therapeutic intervention seems to be an important avenue for combating infections by stimulating the natural defense system of infected individuals. With this perspective, the present study focuses on two immunodominant Leishmania (L.) donovani antigens (triosephosphate isomerase and enolase) previously proved to be potent prophylactic VL vaccine candidates, for generating a recombinant chimeric antigen. This is based on the premise that in a heterogeneous population, a multivalent antigen vaccine would be required for an effective response against leishmaniasis (a complex parasitic disease). The resulting molecule rLdT-E chimeric protein was evaluated for its immunogenicity and immunotherapeutic efficacy. A Th1 stimulating adjuvant BCG was employed with the protein which showed a remarkable 70% inhibition of splenic parasitic multiplication positively correlated with boosted Th1 dominant immune response against lethal L. donovani challenge in hamsters as evidenced by high IFN-γ and TNF-α and low IL-10. In addition, immunological analysis of antibody subclass presented IgG2-based humoral response besides considerable delayed-type hypersensitivity and lymphocyte proliferative responses in rLdT-E/BCG-treated animals. Our observations indicate the potential of the chimera towards its candidature for an effective vaccine against Leishmania donovani infection.
Highlights
Visceral leishmaniasis (VL), a fatal protozoan disease, commonly affects poor communities of the world with prevalence in India, Brazil, Sudan, South Sudan, Ethiopia, Kenya, and Somalia [1]
Recent innovations and decades of endeavor resulted in a diverse pipeline of novel vaccine candidates against VL ranging from traditional live vaccines to advanced recombinant polyprotein and multiantigenic T-cell epitope-based vaccines, in preclinical and clinical trials; translation of these to develop a human administrable vaccine for VL is still arduous
The rLdT-E chimeric protein generated was assessed for its potentiality as a vaccine antigen, and increased in vitro lymphocyte proliferative responses in Leishmania-infected as well as treated hamsters were observed upon stimulation with the chimeric protein as compared to the control Soluble L. donovani (SLD) antigen, substantiating its immunogenicity against Leishmania infection [31, 32]
Summary
Visceral leishmaniasis (VL), a fatal protozoan disease, commonly affects poor communities of the world with prevalence in India, Brazil, Sudan, South Sudan, Ethiopia, Kenya, and Somalia [1]. The expansion of HIV-VL coinfections as well as post-kala-azar dermal leishmaniasis (PKDL) cases has severely influenced the VL epidemiology [3, 4] In these circumstances, wherein the immunity of personnel is suppressed, there is an obligatory need for the development and implementation of therapeutic intervention that could aid in restoring or promoting an effective immune response with resolution of infection and long-lasting protection, presenting a better alternative to chemotherapy. Several proteins from the soluble fraction of the promastigote stage were found to have Th1 stimulatory potential [16, 17] of which enolase and triosephosphate isomerase (TPI) were reported to confer considerable prophylactic efficacy and Th1 skewed immune response against Leishmania challenge [18, 19] These two vital glycolytic enzymes have been considered potential vaccine targets in other diseases as well [20,21,22]. We generated a single recombinant chimeric protein comprising the sequences of enolase and TPI genetically linked in tandem and characterized its possible immunotherapeutic effect on L. donovani-infected hamsters with the aim of contributing towards the design and development of an effective vaccine against visceral leishmaniasis
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