Fernández Álvarez, MaríaHorcajo Iglesias, María Del PilarJiménez Meléndez, AlejandroFerré Pérez, IgnacioOrtega Mora, Luis MiguelÁlvarez García, GemaAngulo Lara, PabloHuertas López, AnaHuertas López, Francisco2024-04-162024-04-162024-03-15Fernández-Álvarez, M.; Horcajo, P.; Jiménez-Meléndez, A.; Lara, P.A.; Huertas-López, A.; Huertas-López, F.; Ferre, I.; Ortega-Mora, L.M.; Álvarez-García, G. Transcriptomics of Besnoitia besnoiti-Infected Fibroblasts Reveals Hallmarks of Early Fibrosis and Cancer Progression. Microorganisms 2024, 12, 586. https://doi.org/ 10.3390/microorganisms120305862076-2607https://hdl.handle.net/20.500.14352/103141Author contributions: G.Á.-G., I.F. and L.M.O.-M. conceived the study and acquired funding for the study; M.F.-Á., A.J.-M. and P.H. carried out the experimental assays; M.F.-Á., P.A.L., A.H.-L. and F.H.-L. performed the bioinformatic and statistical analyses and prepared the figures and tables. M.F.-Á., G.Á.-G. and P.H. drafted the original manuscript. All authors have read and agreed to the published version of the manuscript.Endothelial injury, inflammatory infiltrate and fibrosis are the predominant lesions in the testis of bulls with besnoitiosis that may result in sterility. Moreover, fibroblasts, which are key players in fibrosis, are parasite target cells in a Besnoitia besnoiti chronic infection. This study aimed to decipher the molecular basis that underlies a drift toward fibrosis during the disease progression. Transcriptomic analysis was developed at two times post-infection (p.i.), representative of invasion (12 h p.i.) and intracellular proliferation (32 h p.i.), in primary bovine aorta fibroblasts infected with B. besnoiti tachyzoites. Once the enriched host pathways were identified, we studied the expression of selected differentially expressed genes (DEGs) in the scrotal skin of sterile infected bulls. Functional enrichment analyses of DEGs revealed shared hallmarks of cancer and early fibrosis. Biomarkers of inflammation, angiogenesis, cancer, and MAPK signaling stood out at 12 h p.i. At 32 h p.i., again MAPK and cancer pathways were enriched together with the PI3K–AKT pathway related to cell proliferation. Some DEGs were also regulated in the skin samples of naturally infected bulls (PLAUR, TGFβ1, FOSB). We have identified potential biomarkers and host pathways regulated during fibrosis that may hold prognostic significance and could emerge as potential therapeutic targets.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://www.mdpi.com/2076-2607/12/3/586open access636.09Besnoitia besnoitibovine aorta fibroblastsRNA-Seqearly fibrosisMAPK signalingTGFβcancer progressionVeterinariaGanado vacunoParasitología (Veterinaria)3109 Ciencias Veterinarias3104.02 Bovinos