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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Neospora caninum<\/jats:italic> is an apicomplexan parasite responsible for bovine neosporosis, a major cause of abortion in cattle worldwide. <jats:italic>N. caninum<\/jats:italic> rhoptry protein 2 (NcROP2) has been identified as an essential factor in host cell invasion and parasitophorous vacuole formation, making it a potential target for disease control strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we generated <jats:italic>NcRop2<\/jats:italic> knockout (<jats:italic>Nc\u0394ROP2<\/jats:italic>) mutants using CRISPR\/Cas9 technology to assess their role in parasite virulence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a pregnant mouse model, <jats:italic>Nc\u0394ROP2<\/jats:italic> parasites exhibited reduced virulence, as indicated by increased neonatal survival rates and lower parasite burden in the brain and attenuated clinical signs in the dams compared to the wild-type (Nc-Spain7) parental strain. Additionally, the <jats:italic>Nc\u0394ROP2<\/jats:italic> mutants exhibited impaired proliferation and significantly induced the expression of interferon-stimulated genes in bovine monocyte-derived macrophages infected <jats:italic>in vitro<\/jats:italic> for 60 hours. Transcriptomic analysis further revealed a shift in parasite gene expression, with an upregulation of stress-related and bradyzoite markers. Functional assays confirmed that <jats:italic>Nc<\/jats:italic>\u0394<jats:italic>ROP2<\/jats:italic> parasites were less susceptible to IFN-\u03b3-mediated inhibition and displayed an enhanced ability to convert to the semi-dormant bradyzoite stage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings highlight NcROP2 as a key virulence factor involved in immune evasion and parasite proliferation, providing new insights into <jats:italic>N.\u00a0caninum<\/jats:italic> infection pathogenesis and potential avenues for vaccine development.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1617570","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T05:30:30Z","timestamp":1754976630000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["NcROP2 deletion reduces Neospora caninum virulence by altering parasite stage differentiation and hijacking host immune response"],"prefix":"10.3389","volume":"16","author":[{"given":"Rafael","family":"Amieva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Coronado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Arranz-Sol\u00eds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musa A.","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Collantes-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis 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