Abstract
The Leishmania (Leishmania) donovani nucleoside hydrolase NH36 is the main antigen of the Leishmune® vaccine and one of the promising candidates for vaccination against visceral leishmaniasis. The antigenicity of the N-terminal (F1), the central (F2), or the C-terminal recombinant domain (F3) of NH36 was evaluated using peripheral blood mononuclear cells (PBMC) from individuals infected with L. (L.) infantum from an endemic area of visceral leishmaniasis of Spain. Both NH36 and F1 domains significantly increased the PBMC proliferation stimulation index of cured patients and infected asymptomatic individuals compared to healthy controls. Moreover, F1 induced a 19% higher proliferative response than NH36 in asymptomatic exposed subjects. In addition, in patients cured from visceral leishmaniasis, proliferation in response to NH36 and F1 was accompanied by a significant increase of IFN-γ and TNF-α secretion, which was 42–43% higher, in response to F1 than to NH36. The interleukin 17 (IL-17) secretion was stronger in asymptomatic subjects, in response to F1, as well as in cured cutaneous leishmaniasis after NH36 stimulation. While no IL-10 secretion was determined by F1, a granzyme B increase was detected in supernatants from cured patients after stimulation with either NH36 or F1. These data demonstrate that F1 is the domain of NH36 that induces a recall cellular response in individuals with acquired resistance to the infection by L. (L.) infantum. In addition, F1 and NH36 discriminated the IgG3 humoral response in patients with active visceral leishmaniasis due to L. (L.) donovani (Ethiopia) and L. (L.) infantum (Spain) from that of endemic and non-endemic area controls. NH36 showed higher reactivity with sera from L. (L.) donovani-infected individuals, indicating species specificity. We conclude that the F1 domain, previously characterized as an inducer of the Th1 and Th17 responses in cured/exposed patients infected with L. (L.) infantum chagasi, may also be involved in the generation of a protective response against L. (L.) infantum and represents a potential vaccine candidate for the control of human leishmaniasis alone, or in combination with other HLA epitopes/antigens.
Highlights
Leishmaniasis is a vector-born infectious disease caused by a group of protozoan parasites of the genus Leishmania
Further lymphoproliferation analysis and quantification of cytokines secreted to the supernatants were performed in antigen-stimulated peripheral blood mononuclear cells (PBMC) from additional 10 patients cured from visceral leishmaniasis (CVL) and eight individuals cured from cutaneous leishmaniasis (CCL)
F1 Is the Main Domain of NH36 Recognized by the Lymphoproliferative Response of VL Cured and Asymptomatic Individuals In VL, the cellular immune response to leishmanial antigens is lost during the active disease but is maintained in the infected asymptomatic subjects and cured individuals
Summary
While vaccination has been considered as a very effective tool for the eradication of canine visceral leishmaniasis (canine VL) [4, 5] and four veterinary vaccines were already licensed [6,7,8,9], there is still no vaccine available for use in humans. In Europe, there are two veterinary vaccines, one composed of the 54 kDa native excreted/secreted protein (Canileish) [6] and the other a chimera recombinant multiprotein protein Q, which contains the acidic ribosomal proteins Lip2a, Lip2b, P0, and histone H2A [7] (Latifend). (L.) infantum chagasi (Leish-Tec®) [12] was licensed in Brazil, in 2007 [13] The A2 recombinant protein of L. (L.) infantum chagasi (Leish-Tec®) [12] was licensed in Brazil, in 2007 [13]
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