Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter.
The parasitic liver fluke Fasciola hepatica infests mainly ruminants, but it can also cause fasciolosis in people, who ingest the metacercariae encysted on plants. The drug of choice to treat fasciolosis is triclabendazole (TBZ), which has been on the market for several decades. This is also true fo...
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ftdoajarticles:oai:doaj.org/article:86931656fe754726a2a386904dbf13be 2023-05-15T15:13:27+02:00 Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. Bulut Hamali Sandra Pichler Elisabeth Wischnitzki Klaus Schicker Melanie Burger Marion Holy Kathrin Jaentsch Martina Molin Eva Maria Sehr Oliver Kudlacek Michael Freissmuth 2018-04-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006428 https://doaj.org/article/86931656fe754726a2a386904dbf13be EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5942844?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006428 https://doaj.org/article/86931656fe754726a2a386904dbf13be PLoS Neglected Tropical Diseases, Vol 12, Iss 4, p e0006428 (2018) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2018 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006428 2022-12-31T00:02:39Z The parasitic liver fluke Fasciola hepatica infests mainly ruminants, but it can also cause fasciolosis in people, who ingest the metacercariae encysted on plants. The drug of choice to treat fasciolosis is triclabendazole (TBZ), which has been on the market for several decades. This is also true for the other available drugs. Accordingly, drug-resistant flukes have been emerging at an increasing rate making it desirable to identify alternative drug targets. Here, we focused on the fact that adult F. hepatica persists in the hostile environment of the bile ducts of infected organisms. A common way to render bile acids less toxic is to conjugate them to taurine (2-aminoethanesulfonic acid). We cloned a transporter from the solute carrier-6 (SLC6) family, which was most closely related to the GABA-transporter-2 of other organisms. When heterologously expressed, this F. hepatica transporter supported the high-affinity cellular uptake of taurine (KM = 12.0 ± 0.5 μM) but not of GABA. Substrate uptake was dependent on Na+- and Cl- (calculated stoichiometry 2:1). Consistent with the low chloride concentration in mammalian bile, the F. hepatica transporter had a higher apparent affinity for Cl- (EC50 = 14±3 mM) than the human taurine transporter (EC50 = 55±7 mM). We incubated flukes with unconjugated bile acids in the presence and absence of taurine: taurine promoted survival of flukes; the taurine transporter inhibitor guanidinoethansulfonic acid abolished this protective effect of taurine. Based on these observations, we conclude that the taurine transporter is critical for the survival of liver flukes in the bile. Thus, the taurine transporter represents a candidate drug target. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 12 4 e0006428 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Bulut Hamali Sandra Pichler Elisabeth Wischnitzki Klaus Schicker Melanie Burger Marion Holy Kathrin Jaentsch Martina Molin Eva Maria Sehr Oliver Kudlacek Michael Freissmuth Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The parasitic liver fluke Fasciola hepatica infests mainly ruminants, but it can also cause fasciolosis in people, who ingest the metacercariae encysted on plants. The drug of choice to treat fasciolosis is triclabendazole (TBZ), which has been on the market for several decades. This is also true for the other available drugs. Accordingly, drug-resistant flukes have been emerging at an increasing rate making it desirable to identify alternative drug targets. Here, we focused on the fact that adult F. hepatica persists in the hostile environment of the bile ducts of infected organisms. A common way to render bile acids less toxic is to conjugate them to taurine (2-aminoethanesulfonic acid). We cloned a transporter from the solute carrier-6 (SLC6) family, which was most closely related to the GABA-transporter-2 of other organisms. When heterologously expressed, this F. hepatica transporter supported the high-affinity cellular uptake of taurine (KM = 12.0 ± 0.5 μM) but not of GABA. Substrate uptake was dependent on Na+- and Cl- (calculated stoichiometry 2:1). Consistent with the low chloride concentration in mammalian bile, the F. hepatica transporter had a higher apparent affinity for Cl- (EC50 = 14±3 mM) than the human taurine transporter (EC50 = 55±7 mM). We incubated flukes with unconjugated bile acids in the presence and absence of taurine: taurine promoted survival of flukes; the taurine transporter inhibitor guanidinoethansulfonic acid abolished this protective effect of taurine. Based on these observations, we conclude that the taurine transporter is critical for the survival of liver flukes in the bile. Thus, the taurine transporter represents a candidate drug target. |
format |
Article in Journal/Newspaper |
author |
Bulut Hamali Sandra Pichler Elisabeth Wischnitzki Klaus Schicker Melanie Burger Marion Holy Kathrin Jaentsch Martina Molin Eva Maria Sehr Oliver Kudlacek Michael Freissmuth |
author_facet |
Bulut Hamali Sandra Pichler Elisabeth Wischnitzki Klaus Schicker Melanie Burger Marion Holy Kathrin Jaentsch Martina Molin Eva Maria Sehr Oliver Kudlacek Michael Freissmuth |
author_sort |
Bulut Hamali |
title |
Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
title_short |
Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
title_full |
Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
title_fullStr |
Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
title_full_unstemmed |
Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter. |
title_sort |
identification and characterization of the fasciola hepatica sodium- and chloride-dependent taurine transporter. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2018 |
url |
https://doi.org/10.1371/journal.pntd.0006428 https://doaj.org/article/86931656fe754726a2a386904dbf13be |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 12, Iss 4, p e0006428 (2018) |
op_relation |
http://europepmc.org/articles/PMC5942844?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006428 https://doaj.org/article/86931656fe754726a2a386904dbf13be |
op_doi |
https://doi.org/10.1371/journal.pntd.0006428 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
12 |
container_issue |
4 |
container_start_page |
e0006428 |
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1766344012600442880 |