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
Authors: V N R Das
P Das
Manish K Singh
Chayanika Bordoloi
Pushpanjali
Sarita Kumari
S Narayan
Fauzia Jamal
Amit K Dubey
K Pandey
Shubhankar K Singh
Pushkar Shivam
Journal: Cytokine (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Adaptive immunity; Immunoprophylaxis; Leishmania donovani; Nucleoporins-93 (NUP-93); Th1 response
Affiliations: Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India., Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India; National Institute of Pharmaceutical Education and Research, Hajipur 844102, India., National Institute of Pharmaceutical Education and Research, Hajipur 844102, India., Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India. Electronic address: .

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 (rLd-NUP93) on mononuclear cells in healthy and treated visceral leishmaniasis (VL) patients and on THP-1 cell lines. rLd-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 rLd-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 rLd-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 rLd-NUP93 was an effective immunoprophylactic agent that can be explored in future vaccine design. 

Retracted: No

PubPeer comments:
 duplication of gel images ![file] Disclaimer: These potential image duplications have been detected automatically using ImageTwin http: dx.doi.org 10.1145 3019612.3019875 Although results have been curated, the automatic algorithm may have generated false positive results and cannot take into account all scientific explanations for apparent duplications like stripped and reprobed blots, time series, serial sections and reused controls. ,