Abstract
Leishmania (V.) braziliensis is the etiological agent of Cutaneous (CL) and Mucocutaneous leishmaniasis (ML) in the New World. CL can be more benign but ML can be severe and disfiguring. Immunity to these diseases include hypersensitivity, an enhanced inflammatory response with strong IFN-γ and TNF-α secretion. Additionally, the production of IL-10 which down modulates the immune response is reduced. The Nucleoside hydrolase (NH36) of Leishmania (L.) donovani is the main antigen of the Leishmune veterinary vaccine and its F3 domain induces a CD4+ T cell-mediated protection against L. (L.) infantum chagasi infection. Prevention of L. (L.) amazonensis infection requires in contrast an additional CD8+ T cell mediated response induced by the F1 domain. Consequently, the F1F3 recombinant chimera, which contains both domains cloned in tandem, optimized the vaccine efficacy against L. (L.) amazonensis mouse infection. We compared the efficacies of NH36, F1, F3, and the FIF3 chimera against L. (V.) braziliensis mouse infection. The F1F3 chimera increased the NH36 specific IgA and response before and after infection and the IgG and IgG3 levels after challenge. It also induced a 49% stronger intradermal response to leishmanial antigen (IDR) than NH36 that was positively correlated to the levels of IFN-γ and TNF-α, IgG, IgG2a, IgG2b, and IgG3 anti-NH36 antibodies. However, stronger Th1 responses with elevated IFN-γ/IL-10 and TNF-α/IL-10 ratios were promoted by the F3 and F1 vaccines and detected in infected controls while the F1F3 chimera promoted the highest IL-10 secretion, which reduced the pathological Th1 response, and characterized the induction of a mixed and/or T-cell regulatory response. We identified the epitopes responsible for these immune responses. The F3 vaccine induced the earliest immunity and after challenge, the F1F3 chimera promoted the highest CD4+ and CD8+ cytokine-secreting T cell responses, and the predominant frequencies of multifunctional CD4+ and CD8+IL-2+TNF-α+IFN-γ+ T cells. Also as observed against L. (L.) amazonensis infection, the F1F3 chimera showed the strongest reduction of the ear lesions sizes induced by L. (V.) braziliensis. Our results confirm the potential use of the F1F3 chimera in a multi-species cross-protective vaccine against L. (V.) braziliensis.
Highlights
Leishmaniasis comprises a complex of diseases which are endemic in 98 countries and about 350 million individuals are at risk
We investigated the protective potential of three sc doses of the NH36, F1, F3, or F1F3 recombinant vaccines formulated with saponin, to prevent the development of L. (V.) braziliensis infection in the ears of BALB/c mice
NH36 is a conserved phylogenetic marker of the genus Leishmania [42], a vital enzyme for the metabolism of the DNA of the parasite [43] and a very potent antigen [32, 33, 35, 37,38,39, 44, 45]. It is considered a strong candidate for the development of a cross-protective vaccine against both visceral and cutaneous leishmaniasis of mice and humans [35, 38, 39, 41]
Summary
Leishmaniasis comprises a complex of diseases which are endemic in 98 countries and about 350 million individuals are at risk. The different forms of the disease include: Visceral leishmaniasis (VL), Cutaneous leishmaniasis (CL), Mucosal leishmaniasis (ML), Diffuse cutaneous leishmaniasis (DCL), and Disseminated leishmaniasis (DL) [1]. While VL and DCL represent the most severe forms of the disease and show a characteristic impaired cellular immune response, CL and ML present a Th1 immune response with high secretion of the pro-inflammatory cytokines IFN-γ and TNF-α [2, 3]. CL is considered the most common manifestation of tegumentary leishmaniasis and shows a primary lesion that develops at the site of the bite of the transmitting insect [4,5,6]. ML occurs in 3% of the patients that had previously developed CL, damaging tissues and often with disfiguring lesions on the face [8] which may cause severe psychological problems to such patients. Recent investigations have disclosed that the severity of CL caused by L. (V.) braziliensis is more related to an exacerbated inflammatory response, than to a high parasite burden [8, 10,11,12,13]
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