title: Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions.
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.
authors.affiliation: Institute of Tropical Medicine, Department of Biomedical Sciences, Antwerp, Belgium.|University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Géraldine
authors.identifier: 0000-0003-2295-5564
authors.initials: G
authors.lastname: De Muylder
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
authors.affiliation: Institute of Tropical Medicine, Department of Biomedical Sciences, Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Caljon
authors.affiliation: University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: McKerrow
authors.affiliation: Institute of Tropical Medicine, Department of Biomedical Sciences, Antwerp, Belgium.|Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
mesh_terms: D000818:Animals; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D007896:Leishmaniasis / Q000188:drug therapy; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology*; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics; D014617:Vacuoles / Q000187:drug effects / Q000502:physiology
chemical_list: D018942:Macrolides; D034741:RNA, Small Interfering; D009270:Naloxone; C036978:concanamycin A; C034643:naloxonazine; D025262:Vacuolar Proton-Translocating ATPases