Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions.
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 p...
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ftdoajarticles:oai:doaj.org/article:fcfb8dd78046405aaf1e64e8bf2c95a5 2023-05-15T15:07:35+02:00 Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. Géraldine De Muylder Benoit Vanhollebeke Guy Caljon Alan R Wolfe James McKerrow Jean-Claude Dujardin 2016-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005234 https://doaj.org/article/fcfb8dd78046405aaf1e64e8bf2c95a5 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5201425?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005234 https://doaj.org/article/fcfb8dd78046405aaf1e64e8bf2c95a5 PLoS Neglected Tropical Diseases, Vol 10, Iss 12, p e0005234 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005234 2022-12-31T01:43:19Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 12 e0005234 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Géraldine De Muylder Benoit Vanhollebeke Guy Caljon Alan R Wolfe James McKerrow Jean-Claude Dujardin Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Géraldine De Muylder Benoit Vanhollebeke Guy Caljon Alan R Wolfe James McKerrow Jean-Claude Dujardin |
author_facet |
Géraldine De Muylder Benoit Vanhollebeke Guy Caljon Alan R Wolfe James McKerrow Jean-Claude Dujardin |
author_sort |
Géraldine De Muylder |
title |
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
title_short |
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
title_full |
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
title_fullStr |
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
title_full_unstemmed |
Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions. |
title_sort |
naloxonazine, an amastigote-specific compound, affects leishmania parasites through modulation of host-encoded functions. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0005234 https://doaj.org/article/fcfb8dd78046405aaf1e64e8bf2c95a5 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 12, p e0005234 (2016) |
op_relation |
http://europepmc.org/articles/PMC5201425?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005234 https://doaj.org/article/fcfb8dd78046405aaf1e64e8bf2c95a5 |
op_doi |
https://doi.org/10.1371/journal.pntd.0005234 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
10 |
container_issue |
12 |
container_start_page |
e0005234 |
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1766339055654535168 |