TY - JOUR
T1 - Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel
AU - Clec'h, Winka Le
AU - Chevalier, Frédéric D.
AU - Mattos, Ana Carolina A.
AU - Strickland, Amanda
AU - Diaz, Robbie
AU - McDew-White, Marina
AU - Rohr, Claudia M.
AU - Kinung'hi, Safari
AU - Allan, Fiona
AU - Webster, Bonnie L.
AU - Webster, Joanne P.
AU - Emery, Aidan M.
AU - Rollinson, David
AU - Djirmay, Amadou Garba
AU - Al Mashikhi, Khalid M.
AU - Al Yafae, Salem
AU - Idris, Mohamed A.
AU - Moné, Hélène
AU - Mouahid, Gabriel
AU - LoVerde, Philip
AU - Marchant, Jonathan S.
AU - Anderson, Timothy J.C.
N1 - Publisher Copyright:
© 2021 The Authors.
PY - 2021/12/22
Y1 - 2021/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122006029&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122006029&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abj9114
DO - 10.1126/scitranslmed.abj9114
M3 - Article
C2 - 34936381
AN - SCOPUS:85122006029
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 625
M1 - abj9114
ER -