Mevalonate kinase of Leishmania donovani promotes its survival and plays a pivotal role in pathogenesis.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0370713 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2449 (Electronic) Linking ISSN: 00144894 NLM ISO Abbreviation: Exp Parasitol Subsets: MEDLINE
    • Publication Information:
      Publication: Orlando, FL : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Leishmania donovani*/enzymology ; Leishmania donovani*/pathogenicity ; Leishmania donovani*/genetics ; Leishmania donovani*/physiology ; Mice, Inbred BALB C* ; Leishmaniasis, Visceral*/parasitology ; Leishmaniasis, Visceral*/immunology ; Nitric Oxide*/metabolism ; Macrophages, Peritoneal*/parasitology ; Macrophages, Peritoneal*/enzymology ; Cytokines*/metabolism ; Phosphotransferases (Alcohol Group Acceptor)*/metabolism ; Phosphotransferases (Alcohol Group Acceptor)*/genetics ; Nitric Oxide Synthase Type II*/metabolism; Animals ; Mice ; Arginase/metabolism ; Arginase/genetics ; Female ; Gene Knockdown Techniques
    • Abstract:
      The infectivity of Leishmania is determined by its ability to invade and evade host and its thriving capacity within the macrophage. Our study revealed the role of Leishmania donovani mevalonate kinase (MVK), an enzyme of mevalonate pathway in visceral leishmaniasis pathogenesis. Peritoneal exudate cells (PEC)-derived macrophages from BALB/c mice were infected with wild type (WT), MVK over expressing (MVK OE) and knockdown (KD) parasites and MVK OE parasites were found to be more infective than WT and MVK KD parasites. Incubation of macrophages with MVK OE parasites declined inducible nitric oxide synthase (iNOS) expression as well as nitric oxide (NO) production, both by 2 times in comparison to WT parasites. Moreover, ∼3 fold increase in Arginase1 expression indicated that MVK might induce polarization of macrophage towards M2, favouring the survival of parasite within the macrophages. Post 24 h infection of the macrophages with mutant strains, the levels of different cytokines (TNF-α, IL-12, IL-10 and IFN-γ) were measured. Infection of macrophages with MVK OE parasites showed an increase in the level of anti-inflammatory cytokine: IL-10 while infection with MVK KD parasites exhibited an increase in the level of pro-inflammatory cytokines: TNF-α, IL-12, and IFN-γ. Hence, Leishmania donovani mevalonate kinase (LdMVK) modulates macrophage functions and has a significant role in pathogenesis.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declarations of interest: none.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Leishmania donovani; Macrophages; Mevalonate kinase; Pathogenesis
    • Accession Number:
      31C4KY9ESH (Nitric Oxide)
      0 (Cytokines)
      EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
      EC 2.7.1.36 (mevalonate kinase)
      EC 1.14.13.39 (Nitric Oxide Synthase Type II)
      EC 3.5.3.1 (Arginase)
    • Publication Date:
      Date Created: 20240723 Date Completed: 20240814 Latest Revision: 20240815
    • Publication Date:
      20240815
    • Accession Number:
      10.1016/j.exppara.2024.108800
    • Accession Number:
      39043326