Co-factor-independent phosphoglycerate mutase of Leishmania donovani modulates macrophage signalling and promotes T-cell repertoires bearing epitopes for both MHC-I and MHC-II

• Published in: Parasitology 2018-03, Vol.145 (3), p.292-306
• Main Authors: SINGH, MANISH K., JAMAL, FAUZIA, DUBEY, AMIT K., SHIVAM, PUSHKAR, KUMARI, SARITA, PUSHPANJALI, AHMED, GHUFRAN, DIKHIT, MANAS R., NARAYAN, S., DAS, V. N. R., PANDEY, KRISHNA, SINHA, K. K., DAS, P., SINGH, SHUBHANKAR K.
• Format: Article
• Language: English
• Subjects: Antigens; Brugia malayi; Cell Line; Coenzymes - deficiency; Coenzymes - genetics; Computer Simulation; Cytokines; Cytokines - drug effects; Cytokines - immunology; Epitopes, T-Lymphocyte - drug effects; Epitopes, T-Lymphocyte - immunology; Genes, MHC Class I - immunology; Genes, MHC Class II - immunology; Growth factors; Humans; Interferon; Interleukin-1beta - drug effects; Interleukin-1beta - immunology; Interleukins; Leishmania; Leishmania donovani; Leishmania donovani - enzymology; Leishmania donovani - immunology; Leishmaniasis, Visceral - immunology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - parasitology; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - parasitology; NF-kappa B p50 Subunit - drug effects; NF-kappa B p50 Subunit - genetics; Nitric Oxide; Nitric Oxide Synthase Type II - drug effects; Phosphoglycerate Mutase - genetics; Phosphoglycerate Mutase - immunology; Phosphoglycerate Mutase - pharmacology; Reactive oxygen species; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - pharmacology; Stimulation; Th1 Cells; Vector-borne diseases
• ISSN: 0031-1820; 1469-8161
• DOI: 10.1017/S0031182017001494

Immunoactivation depends upon the antigen potential to modulate T-cell repertoires. The present study has enumerated the effect of 61 kDa recombinant Leishmania donovani co-factor-independent phosphoglycerate mutase (rLd-iPGAM) on mononuclear cells of healthy and treated visceral leishmaniasis subjects as well as on THP-1 cell line. rLd-iPGAM stimulation induced higher expression of interleukin-1β (IL-1β) in the phagocytic cell, its receptor and CD69 on T-cell subsets. These cellular activations resulted in upregulation of host-protective cytokines IL-2, IL-12, IL-17, tumour necrosis factor-α and interferon-γ, and downregulation of IL-4, IL-10 and tumour growth factor-β. This immune polarization was also evidenced by upregulation of nuclear factor-κ light-chain enhancer of activated B cells p50 and regulated expression of suppressor of mother against decapentaplegic protein-4. rLd-iPGAM stimulation also promoted lymphocyte proliferation and boosted the leishmaniacidal activity of macrophages by upregulating reactive oxygen species. It also induced 1·8-fold higher release of nitric oxide (NO) by promoting the transcription of inducible nitric oxide synthase gene. Besides, in silico analysis suggested the presence of major histocompatibility complex class I and II restricted epitopes, which can proficiently trigger CD8+ and CD4+ cells, respectively. This study reports rLd-iPGAM as an effective immunoprophylactic agent, which can be used in future vaccine design.