{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T18:28:02Z","timestamp":1775240882643,"version":"3.50.1"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Anthelmintic drugs are used to treat parasitic roundworm and flatworm infections in humans and other animals. <jats:italic>Caenorhabditis elegans<\/jats:italic> is an established model to investigate anthelmintics used to treat roundworms. In this study, we use <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> to examine the mode of action and the mechanisms of resistance against the flatworm anthelmintic drug praziquantel (PZQ), used to treat trematode and cestode infections. We found that PZQ inhibited development and that this developmental delay varies by genetic background. Interestingly, both enantiomers of PZQ are equally effective against <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic>, but the right-handed PZQ (R-PZQ) is most effective against schistosome infections. We conducted a genome-wide association mapping with 74 wild <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> strains to identify a region on chromosome IV that is correlated with differential PZQ susceptibility. Five candidate genes in this region: <jats:italic>cct-8<\/jats:italic>, <jats:italic>znf-782<\/jats:italic>, <jats:italic>Y104H12D<\/jats:italic>.<jats:italic>4<\/jats:italic>, <jats:italic>Y104H12D<\/jats:italic>.<jats:italic>2<\/jats:italic>, and <jats:italic>cox-18<\/jats:italic>, might underlie this variation. The gene <jats:italic>cct-8<\/jats:italic>, a subunit of the protein folding complex TRiC, has variation that causes a putative protein coding change (G226V), which is correlated with reduced developmental delay. Gene expression analysis suggests that this variant correlates with slightly increased expression of both <jats:italic>cct-8<\/jats:italic> and <jats:italic>hsp-70<\/jats:italic>. Acute exposure to PZQ caused increased expression of <jats:italic>hsp-70<\/jats:italic>, indicating that altered TRiC function might be involved in PZQ responses. To test if this variant affects development upon exposure to PZQ, we used CRISPR-Cas9 genome editing to introduce the V226 allele into the N2 genetic background (G226) and the G226 allele into the JU775 genetic background (V226). These experiments revealed that this variant was not sufficient to explain the effects of PZQ on development. Nevertheless, this study shows that <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> can be used to study PZQ mode of action and resistance mechanisms. Additionally, we show that the TRiC complex requires further evaluation for PZQ responses in <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.pone.0286473","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T17:36:19Z","timestamp":1691688979000},"page":"e0286473","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Praziquantel inhibits Caenorhabditis elegans development and species-wide differences might be cct-8-dependent"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-744X","authenticated-orcid":true,"given":"Janneke","family":"Wit","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clayton M.","family":"Dilks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaotian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen S. Kim","family":"Guisbert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Zdraljevic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Guisbert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-9651","authenticated-orcid":true,"given":"Erik C.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"pone.0286473.ref001","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.pt.2003.11.010","article-title":"Schistosomiasis control: keep taking the tablets","volume":"20","author":"P Hagan","year":"2004","journal-title":"Trends 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