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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.29.610291
preprint
2
Article
Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni
Berger Duncan J.
Park Sang-Kyu
Crellen Thomas
Vianney Tushabe John
Kabatereine Narcis B.
Cotton James A.
Sanya Richard
Elliot Alison
Tukahebwa Edridah M.
Adriko Moses
Standley Claire J.
Gouvras Anouk
Kinung’hi Safari
Haas Helmut
Rabone Muriel
Emery Aidan
Lamberton Poppy H. L.
Webster Bonnie L.
Allan Fiona
Buddenborg Sarah
Berriman Matthew http://orcid.org/0000-0002-9581-0377

Marchant Jonathan S. http://orcid.org/0000-0001-6592-0877

Doyle Stephen R. http://orcid.org/0000-0001-9167-7532

Webster Joanne P.
03 9 2024
2024.08.29.610291https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.29.610291
nihpp-2024.08.29.610291.pdf
Abstract

Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni samples (and the closely related outgroup species, S. rodhaini) from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPM PZQ , a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPM PZQ variants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles.

One Sentence Summary

Population genomics and functional genetics of praziquantel resistance in Schistosoma mansoni
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