Identification and characterization of the Fasciola hepatica sodium- and chloride-dependent taurine transporter.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101291488 Publication Model: eCollection Cited Medium: Internet ISSN: 1935-2735 (Electronic) Linking ISSN: 19352727 NLM ISO Abbreviation: PLoS Negl Trop Dis Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Anthelmintics/*pharmacology ; Bile Acids and Salts/*pharmacology ; Fasciola hepatica/*genetics ; Fascioliasis/*parasitology ; Membrane Glycoproteins/*metabolism ; Membrane Transport Proteins/*metabolism; Amino Acid Sequence ; Animals ; Benzimidazoles/pharmacology ; Cell Line, Tumor ; Chlorides/metabolism ; Fasciola hepatica/drug effects ; Fasciola hepatica/physiology ; Gene Expression ; Genes, Reporter ; Helminth Proteins/genetics ; Helminth Proteins/metabolism ; Humans ; Membrane Glycoproteins/genetics ; Membrane Transport Proteins/genetics ; Phylogeny ; Sequence Alignment ; Sodium/metabolism ; Triclabendazole

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.

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0 (Anthelmintics)
0 (Benzimidazoles)
0 (Bile Acids and Salts)
0 (Chlorides)
0 (Helminth Proteins)
0 (Membrane Glycoproteins)
0 (Membrane Transport Proteins)
148686-53-7 (taurine transporter)
4784C8E03O (Triclabendazole)
9NEZ333N27 (Sodium)

Date Created: 20180428 Date Completed: 20180618 Latest Revision: 20181202

20221213

PMC5942844

10.1371/journal.pntd.0006428

29702654