Visceral leishmaniasis: A novel nuclear envelope protein 'nucleoporins-93 (NUP-93)' from Leishmania donovani prompts macrophage signaling for T-cell activation towards host protective immune response. (January 2019)

• Record Type: Journal Article
• Authors: Singh, Manish K.; Jamal, Fauzia; Dubey, Amit K.; Shivam, Pushkar; Kumari, Sarita; Pushpanjali, ; Bordoloi, Chayanika; Narayan, S.; Das, V.N.R.; Pandey, K.; Das, P.; Singh, Shubhankar K.
• Is Part Of: Cytokine. Volume 113(2019)
• Page Start: 200
• Page End: 215
• Publication Date: 2019-01
• Subjects: Leishmania donovani -- Nucleoporins-93 (NUP-93) -- Adaptive immunity -- Th1 response -- Immunoprophylaxis -- Visceral leishmaniasis; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.07.005
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: Absence of effective commercial vaccine necessitates the exploration of novel immunogenic protein of Leishmania donovani. Cell mediated immunity provides central and key defence mechanism against intracellular leishmania parasite. r Ld- NUP93 boosts the leishmaniacidal activity of macrophage. r Ld- NUP93 evokes the T0 cells towards Th1 cytokine profile. r Ld- NUP93 guides the THP-1 cells to generate host protective immune responses. Abstract: The shift of macrophage and T-cell repertoires towards proinflammatory cytokine signalling ensures the generation of host-protective machinery that is otherwise compromised in cases of the intracellular Leishmania parasite. Different groups have attempted to restore host protective immunity. These vaccine candidates showed good responses and protective effects in murine models, but they generally failed during human trials. In the present study, we evaluated the effect of 97 kDa recombinant nucleoporin-93 of Leishmania donovani (r Ld- NUP93) on mononuclear cells in healthy and treated visceral leishmaniasis (VL) patients and on THP-1 cell lines. r Ld- NUP93 stimulation increased the expression of the early lymphocyte activation marker CD69 on CD4 + and CD8 + T cells. The expression of the host protective pro-inflammatory cytokines IFN-γ, IL-12 and TNF-α was increased, with a corresponding down-regulation of IL-10 and TGF-β upon r Ld- NUP93 stimulation. This immune polarization resulted in the up-regulation of NF-κB p50 with scant expression of SMAD-4. Augmenting lymphocyte proliferation upon priming with r Ld- NUP93 ensured its potential for activation and generation of strong T-cell mediated immune responses. This stimulation extended the leishmanicidal activity of macrophages by releasing high amounts of reactive oxygen species (ROS). Further, the leishmanicidal activity of macrophages was intensified by the elevated production of nitric oxide (NO). The fact that this antigen was earlier reported in circulating immune complexes of VL patients highlights its antigenic importance. In addition, in silico analysis suggested the presence of MHC class I and II-restricted epitopes that proficiently trigger CD8 + and CD4 + T-cells, respectively. This study reported that r Ld- NUP93 was an effective immunoprophylactic agent that can be explored in future vaccine design.