TRPtracker a community database for monitoring praziquantel sensitivity at TRPMPZQ variants

The anthelmintic praziquantel (PZQ) has been used for decades as the clinical therapy for schistosomiasis, and remains the only available drug. As a cheap and effective drug therapy for all human disease-causing Schistosoma species, usage of PZQ underpins mass drug administration strategies aimed at eliminating schistosomiasis as a public health problem by 2030. Concern over the potential emergence of resistance to PZQ is therefore warranted, as it would constitute a major threat to this approach. In terms of molecular adaptations conferring PZQ resistance, variation in the sequence and/or expression of the drug target is an obvious mechanism and should be a priority for surveillance efforts. The target of PZQ is a transient receptor potential ion channel, TRPM_PZQ, which is established as a locus that regulates schistosome sensitivity to PZQ. Here, we describe the establishment of a community resource, ‘TRPtracker’, which coalesces data on TRPM_PZQ natural variants together with measurements of individual TRPM_PZQ variant sensitivity to PZQ assessed by profiling TRPM_PZQ in a heterologous expression system. A compendium of laboratory-generated mutants in TRPM_PZQ is also compiled in the TRPtracker database to delimit regions within TRPM_PZQ that are critical for PZQ sensitivity. Aggregation of data from multiple research groups into TRPtracker catalogues which TRPM_PZQ variants have been functionally profiled, where geographically these variants have been found, their frequency within populations, and their potential impact on PZQ sensitivity. The overall goal is to facilitate rapid community-wide exchange of data to monitor predicted variants of concern that are likely to be associated with decreased PZQ efficacy.