Authors

T Anderson²; F Chevalier²; W Le Clec'h²; E Poole²; YN Tian Bi³; JT Coulibaly³; P Olila⁴; J Oguso⁴; C Orao⁴; B Otieno⁴; H Mazigo⁵; MK Konde⁶; S Knopp¹; SM Ali⁷; EM Ndombi⁴;  ¹ Swiss Tropical and Public Health Institute, Switzerland;  ² Texas Biomedical Research Institute, United States;  ³ University Félix Houphouët-Boigny, Ivory Coast (Cote D'Ivoire);  ⁴ Kenya Institute for Medical Research Institute, Kenya;  ⁵ Catholic University of Health and Allied Sciences, Tanzania;  ⁶ Fondation Santé et Développement Durable (FOSAD) & Centre d'Excellence de Formation & Recherche sur le Paludisme et les Maladies prioritaires en Guinée (CEFORPAG),, Guinea;  ⁷ Public Health Laboratory-Ivo de Carneri, Tanzania

Discussion

We now know that a transient receptor potential ion channel of the melastatin family (TRPM_PZQ)is the target of praziquantel (PZQ), the firstline drug used to treat schistosomiasis. This breakthrough opens up the possibility of field surveillance for praziquantel resistance alleles in schistosome populations. The presence of PZQ resistance alleles is one possible explanation for schistosomiasis hotspots, which are frequently observed in the field. To accurately measure allele frequencies in TRPM_PZQ we collected pools of ~1000 miracidia and designed an array to capture all 37-exons of the TRPM_PZQ gene from both S. mansoni and S. haematobium, which we then sequenced to high read depth. We sequenced TRPM_PZQ in pools of miracidia collected from patients infected with Schistosoma mansoni (75,579 miracidia in 95 pools from 1430 people) or S. haematobium (62,344 miracidia in 76 pools from 1050 people) from several East and West African countries. We found a Q1651H mutation situated adjacent to the PZQ binding site in TRPM_PZQ at 1-5% frequency in several S. haematobium miracidia pools from two adjacent villages in Côte d'Ivoire. This mutation abolishes PZQ binding in a cell-based laboratory assay, so is a mutation of concern. We found a mutation R1843Q that is fixed in West African S. mansoni but at low frequency in East African locations.This mutation results in reduced activation of TRPM_PZQ in cell_-based laboratory assays so may reduce PZQ efficacy in West African locations. These results illustrate the power of pooled sequencing for rapid determination of resistance allele frequency within schistosome populations. Further work is required to determine how these two mutations impact PZQ efficacy in schistosome infected patients.