Imperial College London
Alternate

Joanne P. Webster

Faculty of Medicine, School of Public Health

Visiting Professor
 
 
 
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Contact

 

joanne.webster Website

 
 
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Location

 

Medical SchoolSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Le:2021:10.1101/2021.06.09.447779,
author = {Le, Clech W and Chevalier, FD and Mattos, ACA and Strickland, A and Diaz, R and McDew-White, M and Rohr, CM and Kinunghi, S and Allan, F and Webster, BL and Webster, JP and Emery, AM and Rollinson, D and Djirmay, AG and Al, Mashikhi KM and Yafae, SA and Idris, MA and Moné, H and Mouahid, G and LoVerde, P and Marchant, JS and Anderson, TJC},
doi = {10.1101/2021.06.09.447779},
title = {Genetic analysis of praziquantel response in schistosome parasites implicates a Transient Receptor Potential channel},
url = {http://dx.doi.org/10.1101/2021.06.09.447779},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>Mass treatment with praziquantel (PZQ) monotherapy is the mainstay for schistosomiasis treatment. 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 <jats:italic>Schistosoma mansoni</jats:italic> populations is unknown. We examined the genetic basis of variation in PZQ response in a <jats:italic>S. mansoni</jats:italic> population (SmLE-PZQ-R) selected with PZQ in the laboratory: 35% of these worms survive high dose (73 µg/mL) PZQ treatment. We used genome wide association to map loci underlying PZQ response. The major chr. 3 peak contains a transient receptor potential (<jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic>) channel (Smp_246790), activated by nanomolar concentrations of PZQ. PZQ response shows recessive inheritance and marker-assisted selection of parasites at a single <jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic> SNP enriched populations of PZQ-resistant (PZQ-ER) and sensitive (PZQ-ES) parasites showing >377 fold difference in PZQ response. The PZQ-ER parasites survived treatment in rodents better than PZQ-ES. Resistant parasites show 2.25-fold lower expression of <jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic> than sensitive parasites. Specific chemical blockers of <jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic> enhanced PZQ resistance, while <jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic> activators increased sensitivity. A single SNP in <jats:italic>Sm.TRPM<jats:sub>PZQ</jats:sub></jats:italic> differentiated PZQ-ER and PZQ-ES lines, but mutagenesis showed this was not involved in PZQ-response, suggesting linked regulatory changes. We surveyed <jats:
AU  - Le,Clech W
AU  - Chevalier,FD
AU  - Mattos,ACA
AU  - Strickland,A
AU  - Diaz,R
AU  - McDew-White,M
AU  - Rohr,CM
AU  - Kinunghi,S
AU  - Allan,F
AU  - Webster,BL
AU  - Webster,JP
AU  - Emery,AM
AU  - Rollinson,D
AU  - Djirmay,AG
AU  - Al,Mashikhi KM
AU  - Yafae,SA
AU  - Idris,MA
AU  - Moné,H
AU  - Mouahid,G
AU  - LoVerde,P
AU  - Marchant,JS
AU  - Anderson,TJC
DO  - 10.1101/2021.06.09.447779
PY  - 2021///
TI  - Genetic analysis of praziquantel response in schistosome parasites implicates a Transient Receptor Potential channel
UR  - http://dx.doi.org/10.1101/2021.06.09.447779
ER  -
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