{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:27:51Z","timestamp":1772760471581,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel","doi-asserted-by":"publisher","award":["303624\/2021-3"],"award-info":[{"award-number":["303624\/2021-3"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Council for Scientific and Technological Development","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"National Council for Scientific and Technological Development","award":["303624\/2021-3"],"award-info":[{"award-number":["303624\/2021-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Haemonchus contortus is a highly pathogenic blood-sucking nematode from the abomasum of small ruminants. To develop effective control strategies, it is essential to understand the initial mechanisms involved in host resistance to this parasite. In this study, we used computational tools to analyze the complement and coagulation pathways generated from RNA sequencing of abomasal tissue from resistant (Santa Ines) and susceptible (Ile de France) young sheep artificially infected with H. contortus. Thirty-two differentially expressed genes annotated to the ovine genome were associated with the complement and coagulation cascades, of which 29 of them were overexpressed in Santa Ines. Our data identified potential markers for resistance trait selection in sheep, such as C3 (complement C3), F3 (tissue factor), F5 (coagulation factor V), CFB (complement factor B), and CFI (complement factor I). Santa Ines may have a more robust coagulation system, being activated by extrinsic pathways associated with tissue damage. The complement may act as a mediator of the innate immunity, and its activation in Santa Ines is associated with the classical, the lectin, and the alternative pathway. Finally, resistant Santa Ines lambs had a polygenic overexpressed architecture controlling both complement and coagulation cascades, which probably contributed to the early-onset protection against H. contortus.<\/jats:p>","DOI":"10.3390\/pathogens14050447","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:44:58Z","timestamp":1746171898000},"page":"447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Complement and Coagulation Cascade Activation Regulates the Early Inflammatory Mechanism of Resistance of Suckling Lambs Against Haemonchus contortus"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0810-1434","authenticated-orcid":false,"given":"Jos\u00e9 Gabriel G.","family":"Lins","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, S\u00e3o Paulo State University (UNESP), Botucatu 18618-681, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-5501","authenticated-orcid":false,"given":"Alessandro F. T.","family":"Amarante","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Biodiversity, Institute of Biosciences, S\u00e3o Paulo State University (UNESP), Botucatu 18618-689, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Arsenopoulos, K.V., Fthenakis, G.C., Katsarou, E.I., and Papadopoulos, E. (2021). Haemonchosis: A Challenging Parasitic Infection of Sheep and Goats. Animals, 11.","DOI":"10.3390\/ani11020363"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109734","DOI":"10.1016\/j.vetpar.2022.109734","article-title":"Early-onset immune response to Haemoncus contortus infection in resistant Santa Ines sucking lambs compared with susceptible Ile de France","volume":"307\u2013308","author":"Lins","year":"2022","journal-title":"Vet. Parasitol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ijpara.2023.06.008","article-title":"Abomasal RNA-seq reveals a strong local cell response of suckling lambs with resistance against Haemonchus contortus","volume":"53","author":"Lins","year":"2023","journal-title":"Int. J. Parasitol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105337","DOI":"10.1016\/j.dci.2025.105337","article-title":"Dynamics of immune functional mechanisms and their roles in promoting host resistance to Haemonchus contortus infection in suckling lambs","volume":"164","author":"Lins","year":"2025","journal-title":"Dev. Comp. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nrmicro1824","article-title":"Complement evasion by human pathogens","volume":"6","author":"Lambris","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/cr.2009.139","article-title":"Complement and its role in innate and adaptive immune responses","volume":"20","author":"Dunkelberger","year":"2010","journal-title":"Cell Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13567-019-0622-6","article-title":"Transcriptome analysis unraveled potential mechanisms of resistance to Haemonchus contortus infection in Merino sheep populations bred for parasite resistance","volume":"50","author":"Zhang","year":"2019","journal-title":"Vet. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kenawy, H.I., Boral, I., and Bevington, A. (2015). Complement-coagulation cross-talk: A potential mediator of the physiological activation of complement by low pH. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00215"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sikorski, P.M., Commodaro, A.G., and Grigg, M.E. (2021). A Protective and Pathogenic Role for Complement During Acute Toxoplasma gondii Infection. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.634610"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.molimm.2022.05.118","article-title":"How to get away with murder: The multiple strategies employed by pathogenic protozoa to avoid complement killing","volume":"149","author":"Horta","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110813","DOI":"10.1016\/j.vetimm.2024.110813","article-title":"Expression of Toll-like receptors in Haemonchus contortus-resistant sheep: An innate immune parameter for host defense against gastrointestinal nematode infection","volume":"275","author":"Kumar","year":"2024","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wen, Z., Zhang, Y., Feng, J., Aimulajiang, K., Aleem, M.T., Lu, M., Xu, L., Song, X., Li, X., and Yan, R. (2022). Excretory\/secretory proteins inhibit host immune responses by downregulating the TLR4\/NF-\u03baB\/MAPKs signaling pathway: A possible mechanism of immune evasion in parasitic nematode Haemonchus contortus. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1013159"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1159\/000227805","article-title":"Interactions of ficolin and mannose-binding lectin with fibrinogen\/fibrin augment the lectin complement pathway","volume":"2","author":"Endo","year":"2010","journal-title":"J. Innate Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium (2021). The Gene Ontology resource: Enriching a GOld mine. Nucleic Acids Res., 49, D325\u2013D334.","DOI":"10.1093\/nar\/gkaa1113"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: Integrating viruses and cellular organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Goedhart, J., and Luijsterburg, M.S. (2020). VolcaNoseR is a web app for creating, exploring, labelling and sharing volcano plots. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-76603-3"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape, a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/bioinformatics\/btm554","article-title":"Computing topological parameters of biological networks","volume":"24","author":"Assenov","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bader, G.D., and Hogue, C.W.V. (2003). An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-2"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., and Lin, C.Y. (2014). cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol., 8.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"baaa062","DOI":"10.1093\/database\/baaa062","article-title":"NCBI Taxonomy: A comprehensive update on curation, resources and tools","volume":"2020","author":"Schoch","year":"2020","journal-title":"Database"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e927917","DOI":"10.12659\/MSM.927917","article-title":"Bioinformatics analysis of differentially expressed genes and protein-protein interaction networks associated with functional pathways in ulcerative colitis","volume":"27","author":"Cao","year":"2021","journal-title":"Med. Sci. Monit."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5628","DOI":"10.4049\/jimmunol.0903678","article-title":"Molecular intercommunication between the complement and coagulation systems","volume":"185","author":"Amara","year":"2010","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00281-011-0280-x","article-title":"Interactions between coagulation and complement\u2014Their role in inflammation","volume":"34","author":"Oikonomopoulou","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0065-308X(00)45005-0","article-title":"The immunobiology of gastrointestinal nematode infections in ruminants","volume":"45","author":"Balic","year":"2000","journal-title":"Adv. Parasitol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0021-9975(65)90048-4","article-title":"Pathogenesis of experimental haemonchosis in sheep, with special reference to the development of resistance","volume":"75","author":"Charleston","year":"1965","journal-title":"J. Comp. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S0368-1742(64)80040-0","article-title":"Abomasal bleeding caused by immature stages of Haemonchus contortus in sheep showing \u2018age resistance\u2019","volume":"74","author":"Brambell","year":"1964","journal-title":"J. Comp. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1152\/physiol.00059.2005","article-title":"The interaction between pathogens and the host coagulation system","volume":"21","author":"Sun","year":"2006","journal-title":"Physiology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hulshof, A.M., Hemker, H.C., Spronk, H.M.H., Henskens, Y.M.C., and Ten Cate, H. (2021). Thrombin-fibrin(ogen) interactions, host defense and risk of thrombosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052590"},{"key":"ref_41","unstructured":"Hoffman, R., Benz, E., Shattil, S.J., Furie, B., Cohen, H.J., Silberstein, L.E., and McGlave, P. (2005). Hematology: Basic Principles and Practice, Elsevier Churchill Livingstone."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1440-1797.2009.01128.x","article-title":"Review article: Coagulation cascade and therapeutics update: Relevance to nephrology. Part 1: Overview of coagulation, thrombophilias and history of anticoagulants","volume":"14","author":"Adams","year":"2009","journal-title":"Nephrology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tritten, L., Gillis-Germitsch, N., Kockmann, T., and Schnyder, M. (2021). Quantitative proteomics analysis of Angiostrongylus vasorum-induced alterations in dog serum sheds light on the pathogenesis of canine angiostrongylosis. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-79459-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00281-011-0290-8","article-title":"Fibrinogen as a key regulator of inflammation in disease","volume":"34","author":"Davalos","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"ref_45","unstructured":"Janeway, C.A., Travers, P., Walport, M., and Shlomchik, M.J. (2001). Immunobiology: The Immune System in Health and Disease, Garland Science. [5th ed.]."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.4049\/jimmunol.162.2.1032","article-title":"The mast cell as site of tissue-type plasminogen activator expression and fibrinolysis","volume":"162","author":"Sillaber","year":"1999","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.vetimm.2010.11.008","article-title":"Characterization of the sheep complement factor B gene (CFB)","volume":"140","author":"Qin","year":"2011","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Guo, Z., Gonz\u00e1lez, J.F., Hernandez, J.N., McNeilly, T.N., Corripio-Miyar, Y., Frew, D., Morrison, T., Yu, P., and Li, R.W. (2016). Possible mechanisms of host resistance to Haemonchus contortus infection in sheep breeds native to the Canary Islands. Sci. Rep., 6.","DOI":"10.1038\/srep26200"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.exppara.2010.03.002","article-title":"Haemonchus contortus: Cloning and characterization of serpin","volume":"125","author":"Yi","year":"2010","journal-title":"Exp. Parasitol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Bobardt, S.D., Dillman, A.R., and Nair, M.G. (2020). The two faces of nematode infection: Virulence and immunomodulatory molecules from nematode parasites of mammals, insects and plants. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.577846"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/j.1365-3024.2008.01028.x","article-title":"Haemonchus contortus calreticulin binds to C-reactive protein of its host, a novel survival strategy of the parasite","volume":"30","author":"Suchitra","year":"2008","journal-title":"Parasite Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.0105-2896.2004.0123.x","article-title":"The lectin-complement pathway\u2014Its role in innate immunity and evolution","volume":"198","author":"Fujita","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13567-020-00790-0","article-title":"Proteomic analysis revealed T cell hyporesponsiveness induced by Haemonchus contortus excretory and secretory proteins","volume":"51","author":"Lu","year":"2020","journal-title":"Vet. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.imbio.2010.02.005","article-title":"Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation","volume":"216","author":"Takahashi","year":"2011","journal-title":"Immunobiology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/pim.12273","article-title":"The N-terminal segment of glyceraldehyde-3-phosphate dehydrogenase of Haemonchus contortus interacts with complements C1q and C3","volume":"37","author":"Vedamurthy","year":"2015","journal-title":"Parasite Immunol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/5\/447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:25:42Z","timestamp":1760030742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/5\/447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,1]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["pathogens14050447"],"URL":"https:\/\/doi.org\/10.3390\/pathogens14050447","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,1]]}}}