We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel.
- Authors
Le Clec'h, Winka; Chevalier, Frédéric D.; Mattos, Ana Carolina A.; Strickland, Amanda; Diaz, Robbie; McDew-White, Marina; Rohr, Claudia M.; Kinung'hi, Safari; Allan, Fiona; Webster, Bonnie L.; Webster, Joanne P.; Emery, Aidan M.; Rollinson, David; Djirmay, Amadou Garba; Al Mashikhi, Khalid M.; Al Yafae, Salem; Idris, Mohamed A.; Moné, Hélène; Mouahid, Gabriel; LoVerde, Philip
- Abstract
Praziquantel's target: Praziquantel (PZQ) is a critical antiparasitic drug used to treat schistosomiasis and other parasitic helminths, but its mechanism has not been resolved. A pair of manuscripts by Park et al. and Le Clec'h et al. identified a Schistosoma mansoni transient receptor potential melastatin ion channel (TRPMPZQ) as the target of PZQ. Park et al. characterized a PZQ binding pocket in TRPMPZQ using ligand-based screening and targeted mutagenesis and confirmed that it was broadly conserved in other parasitic flatworms. Le Clec'h et al. used a genome-wide association screen and marker-assisted selection to identify TRPMPZQ as being responsible for variation in PZQ sensitivity and examine sequence variation in TRPMPZQ from field isolates. Together, these papers robustly confirm that TRPMPZQ is the molecular target of PZQ and provide critical information for monitoring PZQ resistance in the field. Mass drug administration with praziquantel (PZQ) monotherapy is considered the mainstay for control and elimination of the parasites causing schistosomiasis in humans. This drug shows imperfect cure rates in the field, and parasites showing reduced PZQ response can be selected in the laboratory, but the extent of resistance in Schistosoma mansoni populations is unknown. We examined the genetic basis of the variation in response in a PZQ-selected S. mansoni population (SmLE-PZQ-R) in which 35% of the parasitic worms survive high-dose PZQ (73 micrograms per milliliter) treatment. We used genome-wide association to map loci underlying PZQ response and identified a transient receptor potential (Sm.TRPMPZQ) channel (Smp_246790) within the major chromosome 3 peak that is activated by nanomolar concentrations of PZQ. The PZQ response showed recessive inheritance and marker-assisted selection of parasites at a single Sm.TRPMPZQ SNP that produced populations of PZQ-enriched resistant (PZQ-ER) and PZQ-enriched sensitive (PZQ-ES) parasites, exhibiting >377-fold difference in PZQ response. The PZQ-ER parasites survived treatment in rodents at higher frequencies compared with PZQ-ES, and resistant parasites exhibited 2.25-fold lower expression of Sm.TRPMPZQ relative to sensitive parasites. Specific chemical blockers of Sm.TRPMPZQ enhanced PZQ resistance, whereas Sm.TRPMPZQ activators increased sensitivity. We surveyed Sm.TRPMPZQ sequence variations in 259 parasites from different global sites and identified one nonsense mutation that resulted in a truncated protein with no PZQ binding site. Our results demonstrate that Sm.TRPMPZQ underlies variation in PZQ responses in S. mansoni and provides an approach for monitoring emerging PZQ-resistant alleles in schistosome elimination programs.
- Subjects
TRP channels; PARASITES; SCHISTOSOMA mansoni; HELMINTHS; PRAZIQUANTEL; GENOME-wide association studies; NONSENSE mutation
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 625, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abj9114