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To address the critical gaps in understanding toltrazuril resistance and possibilities of early diagnostics, our study investigated the genetic basis of resistance through whole-genome DNA sequencing and transcriptome analysis of two <jats:italic>C. suis<\/jats:italic> strains, the toltrazuril-susceptible Wien-I and the resistant Holland-I. Additionally, we studied the mitochondrial genome and analysed mitochondrial gene expression in both strains. Our results show that genes encoding proteins involved in host-cell invasion displayed variable expression patterns and genetic mutations, suggesting adaptive changes in invasion mechanisms. Moreover, substantial fluctuations in the expression of genes linked to retrotransposons, accompanied by genetic alterations, were observed, highlighting their potential involvement in genomic rearrangements. Finally, our mitochondrial genome analyses revealed important insights into its genetic organization and conservation. Notably, the marked downregulation of CoI, CoIII and Cytb mRNA levels in the resistant strain Holland-I upon toltrazuril exposure highlights the dynamic response of mitochondrial genes to toltrazuril. These mitochondrial adaptations appear to be closely linked to the parasite drug resistance mechanism, potentially facilitating its survival under pharmacological stress. These findings enhance our knowledge of drug resistance mechanisms in Coccidia and highlight the need for novel management strategies, leading to the development of targeted treatments and controls.<\/jats:p>","DOI":"10.1038\/s41598-025-89372-8","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T07:56:32Z","timestamp":1739519792000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering the code of resistance: a genomic and transcriptomic exploration of the Cystoisospora suis Holland-I strain"],"prefix":"10.1038","volume":"15","author":[{"given":"Teresa","family":"Cruz-Bustos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baerbel","family":"Ruttkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Joachim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"89372_CR1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3389\/fvets.2015.00068","volume":"2","author":"A Shrestha","year":"2015","unstructured":"Shrestha, A. et al. 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