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- Title
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions.
- Authors
De Muylder, Géraldine; Vanhollebeke, Benoit; Caljon, Guy; Wolfe, Alan R.; McKerrow, James; Dujardin, Jean-Claude
- Abstract
Host-directed therapies (HDTs) constitute promising alternatives to traditional therapy that directly targets the pathogen but is often hampered by pathogen resistance. HDT could represent a new treatment strategy for leishmaniasis, a neglected tropical disease caused by the obligate intracellular parasite Leishmania. This protozoan develops exclusively within phagocytic cells, where infection relies on a complex molecular interplay potentially exploitable for drug targets. We previously identified naloxonazine, a compound specifically active against intracellular but not axenic Leishmania donovani. We evaluated here whether this compound could present a host cell-dependent mechanism of action. Microarray profiling of THP-1 macrophages treated with naloxonazine showed upregulation of vATPases, which was further linked to an increased volume of intracellular acidic vacuoles. Treatment of Leishmania-infected macrophages with the vATPase inhibitor concanamycin A abolished naloxonazine effects, functionally demonstrating that naloxonazine affects Leishmania amastigotes indirectly, through host cell vacuolar remodeling. These results validate amastigote-specific screening approaches as a powerful way to identify alternative host-encoded targets. Although the therapeutic value of naloxonazine itself is unproven, our results further demonstrate the importance of intracellular acidic compartments for host defense against Leishmania, highlighting the possibility of targeting this host cell compartment for anti-leishmanial therapy.
- Subjects
OPIOID receptors; AMASTIGOTES; LEISHMANIASIS treatment; TROPICAL medicine; PATHOGENIC microorganisms; PROTOZOAN disease treatment
- Publication
PLoS Neglected Tropical Diseases, 2016, Vol 10, Issue 12, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0005234