Abstract
Visceral leishmaniasis, caused by Leishmania (L.) donovani and L. infantum protozoan parasites, can provoke overwhelming and protracted epidemics, with high case-fatality rates. An effective vaccine against the disease must rely on the generation of a strong and long-lasting T cell immunity, mediated by CD4+ TH1 and CD8+ T cells. Multi-epitope peptide-based vaccine development is manifesting as the new era of vaccination strategies against Leishmania infection. In this study, we designed chimeric peptides containing HLA-restricted epitopes from three immunogenic L. infantum proteins (cysteine peptidase A, histone H1, and kinetoplastid membrane protein 11), in order to be encapsulated in poly(lactic-co-glycolic) acid nanoparticles with or without the adjuvant monophosphoryl lipid A (MPLA) or surface modification with an octapeptide targeting the tumor necrosis factor receptor II. We aimed to construct differentially functionalized peptide-based nanovaccine candidates and investigate their capacity to stimulate the immunomodulatory properties of dendritic cells (DCs), which are critical regulators of adaptive immunity generated upon vaccination. According to our results, DCs stimulation with the peptide-based nanovaccine candidates with MPLA incorporation or surface modification induced an enhanced maturation profile with prominent IL-12 production, promoting allogeneic T cell proliferation and intracellular production of IFNγ by CD4+ and CD8+ T cell subsets. In addition, DCs stimulated with the peptide-based nanovaccine candidate with MPLA incorporation exhibited a robust transcriptional activation, characterized by upregulated genes indicative of vaccine-driven DCs differentiation toward type 1 phenotype. Immunization of HLA A2.1 transgenic mice with this peptide-based nanovaccine candidate induced peptide-specific IFNγ-producing CD8+ T cells and conferred significant protection against L. infantum infection. Concluding, our findings supported that encapsulation of more than one chimeric multi-epitope peptides from different immunogenic L. infantum proteins in a proper biocompatible delivery system with the right adjuvant is considered as an improved promising approach for the development of a vaccine against VL.
Highlights
Leishmaniasis, a group of vector-borne parasitic diseases caused by dimorphic protozoan flagellates of the genus Leishmania, is highly diverse and complex with a wide spectrum of clinical forms in humans, ranging from the self-healing cutaneous leishmaniasis (CL) to the potentially fatal visceral leishmaniasis (VL)
Synthetic chimeric peptides were dissolved in DMSO or dH2O, Table 1 | Chimeric peptides containing multi-epitope peptides of the Leishmania infantum immunogenic proteins cysteine peptidase A (CPA), histone H1, and kinetoplastid membrane protein 11 (KMP-11)
Immunoinformatics analyses based on algorithms that predict with high accuracy immunodominant epitopes on protein antigens could greatly enhance “polytope vaccine” design and development against infectious diseases, such as VL, since the most efficient immune response to pathogens is derived from different T cells that respond to an ensemble of pathogenderived specific epitopes [47]
Summary
Leishmaniasis, a group of vector-borne parasitic diseases caused by dimorphic protozoan flagellates of the genus Leishmania, is highly diverse and complex with a wide spectrum of clinical forms in humans, ranging from the self-healing cutaneous leishmaniasis (CL) to the potentially fatal visceral leishmaniasis (VL). In South Europe, Central, and South America, VL is caused by Leishmania (L.) infantum (synonym L. chagasi) and is transmitted as a zoonosis with the domestic dog serving as the main reservoir of the parasite, especially in the urban and suburban areas [3]. Current control tactics for VL rely on chemotherapy to alleviate the disease and on vector control to reduce transmission. Since the arsenal of drugs available is limited and chemotherapy gathers many disadvantages with most prominent the toxicity and the emergence of resistance, the development of a prophylactic, safe, and cost affordable vaccine is considered high priority. The success of vaccine development depends on understanding the immunology of host–pathogen interactions, choosing appropriate antigenic candidates, and selecting the right adjuvant and/or delivery vehicle
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