{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T18:21:15Z","timestamp":1776709275053,"version":"3.51.2"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Spanish Ministry of Education, Culture and Sport","award":["FPU19\/03969"],"award-info":[{"award-number":["FPU19\/03969"]}]},{"name":"University of Castile-La Mancha and FEDER","award":["2022-GRIN-34227"],"award-info":[{"award-number":["2022-GRIN-34227"]}]},{"name":"Spanish MINECO","award":["AGL2014-56305"],"award-info":[{"award-number":["AGL2014-56305"]}]},{"name":"University of Cordoba and Junta of Andalusia","award":["UCO-FEDER-1381385-R"],"award-info":[{"award-number":["UCO-FEDER-1381385-R"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Vet Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Caprine tuberculosis (TB) causes a zoonotic disease with significant economic and health implications. However, excluding some regions, goat herds are not subjected to official TB eradication programs. Implementing vaccination protocols for this species could provide a complementary and effective control strategy against TB. We assessed the protective efficacy and immune response associated with a heat-inactivated\n                    <jats:italic>Mycobacterium bovis<\/jats:italic>\n                    (\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>bovis<\/jats:italic>\n                    )-based immunostimulant (HIMB) applied intramuscularly against caprine pulmonary TB on 20 kid goats (10 immunized, 10 controls) naturally exposed to\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>caprae<\/jats:italic>\n                    infected goats for 10\u00a0months. TB-compatible lung lesions were assessed, alongside a local immune response analysis by immunohistochemistry of cell populations (Macrophages (M\u03a6s), neutrophils, T, and B lymphocytes) and associated immune mediators (iNOS, TNF-\u03b1, IL-1\u03b1, IL-6, IFN-\u03b3, TGF-\u03b2, IL-4). In the control group, 60% of the animals showed TB compatible lesions, compared with 40% of the immunized animals, which also showed a 78% reduction (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03) in the lesion severity score. Moreover, immunized animals showed a higher number of M1 M\u03a6s (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03), producers of iNOS, as well as a higher expression of TNF\u03b1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04) and IL-1\u03b1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03). These mediators play a key role in the activation of a Th1-type cellular immune responses effective against mycobacteria, associated with a response of T lymphocytes expressing IFN\u03b3, whose response was increased in the immunized group (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.05). These results suggest that immunization with HIMB reduced the number and severity of TB-associated pulmonary lesions, which could be linked with an enhanced production of immune mediators with an essential role in the activation of M\u03a6s with bactericidal functions.\n                  <\/jats:p>","DOI":"10.1186\/s13567-025-01634-5","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:36:47Z","timestamp":1762252607000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective effect of heat-inactivated Mycobacterium bovis applied intramuscularly is associated with enhanced lung immune response in caprine tuberculosis"],"prefix":"10.1186","volume":"56","author":[{"given":"Irene","family":"Agull\u00f3-Ros","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonor","family":"Mu\u00f1oz-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1lvaro","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Bezos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iker A.","family":"Sevilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inmaculada","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseba","family":"Garrido","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Rodr\u00edguez-Bertos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Dom\u00ednguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram\u00f3n","family":"Juste","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas","family":"Dom\u00ednguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Gort\u00e1zar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda A.","family":"Risalde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"1634_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetimm.2022.110486","volume":"252","author":"DM Cooke","year":"2022","unstructured":"Cooke DM, Goosen WJ, Witte C, Miller MA (2022) Field evaluation of the tuberculin skin test for the detection of Mycobacterium tuberculosis complex infection in communal goats (Capra hircus) in KwaZulu-Natal, South Africa. Vet Immunol Immunopathol 252:110486","journal-title":"Vet Immunol Immunopathol"},{"key":"1634_CR2","doi-asserted-by":"publisher","first-page":"991","DOI":"10.15212\/ZOONOSES-2021-0021","volume":"2","author":"F Huang","year":"2022","unstructured":"Huang F, Zhao Y (2022) Global control of tuberculosis: current status and future prospects. Zoonoses 2:991","journal-title":"Zoonoses"},{"key":"1634_CR3","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.vetimm.2018.03.006","volume":"199","author":"J Bezos","year":"2018","unstructured":"Bezos J, Roy \u00c1, Infantes-Lorenzo JA, Gonz\u00e1lez I, Venteo \u00c1, Romero B, Grau A, M\u00ednguez O, Dom\u00ednguez L, de Juan L (2018) The use of serological tests in combination with the intradermal tuberculin test maximizes the detection of tuberculosis infected goats. Vet Immunol Immunopathol 199:43\u201352","journal-title":"Vet Immunol Immunopathol"},{"key":"1634_CR4","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1136\/vr.101347","volume":"172","author":"S Napp","year":"2013","unstructured":"Napp S, Allepuz A, Mercader I, Nofrar\u00edas M, L\u00f3pez-Soria S, Domingo M, Romero B, Bezos J, P\u00e9rez de Val B (2013) Evidence of goats acting as domestic reservoirs of bovine tuberculosis. Vet Rec 172:663\u2013663","journal-title":"Vet Rec"},{"key":"1634_CR5","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.rvsc.2013.04.019","volume":"95","author":"G Zanardi","year":"2013","unstructured":"Zanardi G, Boniotti MB, Gaffuri A, Casto B, Zanoni M, Pacciarini ML (2013) Tuberculosis transmission by Mycobacterium bovis in a mixed cattle and goat herd. Res Vet Sci 95:430\u2013433","journal-title":"Res Vet Sci"},{"key":"1634_CR6","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.prevetmed.2018.08.015","volume":"159","author":"D Cano-Terriza","year":"2018","unstructured":"Cano-Terriza D, Risalde MA, Rodr\u00edguez-Hern\u00e1ndez P, Napp S, Fern\u00e1ndez-Morente M, Moreno I, Bezos J, Fern\u00e1ndez-Molera V, S\u00e1ez JL, Garc\u00eda-Bocanegra I (2018) Epidemiological surveillance of Mycobacterium tuberculosis complex in extensively raised pigs in the south of Spain. Prev Vet Med 159:87\u201391","journal-title":"Prev Vet Med"},{"key":"1634_CR7","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.smallrumres.2017.11.010","volume":"158","author":"E Vidal","year":"2018","unstructured":"Vidal E, Grasa M, Per\u00e1lvarez T, Mart\u00edn M, Mercader I, de Val BP (2018) Transmission of tuberculosis caused by Mycobacterium caprae between dairy sheep and goats. Small Rumin Res 158:22\u201325","journal-title":"Small Rumin Res"},{"key":"1634_CR8","doi-asserted-by":"publisher","first-page":"2200852","DOI":"10.2807\/1560-7917.ES.2023.28.12.2200852","volume":"28","author":"M Mart\u00ednez-Lirola","year":"2023","unstructured":"Mart\u00ednez-Lirola M, Herranz M, Buenestado Serrano S, Rodr\u00edguez-Grande C, Dominguez Inarra E, Garrido-C\u00e1rdenas JA, Correa Ruiz AM, Berm\u00fadez MP, Causse Del R\u00edo M, Gonz\u00e1lez Gal\u00e1n V, Lir\u00f3 Armenteros J, Viudez Mart\u00ednez JM, Vallejo-Godoy S, Esteban Garc\u00eda AB, Cabezas Fern\u00e1ndez MT, Mu\u00f1oz P, P\u00e9rez Lago L, Garc\u00eda de Viedma D (2023) A One Health approach revealed the long-term role of Mycobacterium caprae as the hidden cause of human tuberculosis in a region of Spain, 2003 to 2022. Euro Surveill 28:2200852","journal-title":"Euro Surveill"},{"key":"1634_CR9","unstructured":"MAPA (2024a) Programa Nacional de Erradicaci\u00f3n de Tuberculosis bovina 2024 (Infecci\u00f3n por el complejo Mycobacterium tuberculosis). https:\/\/www.mapa.gob.es\/es\/ganaderia\/temas\/sanidad-animal-higiene-ganadera\/programatb2024_tcm30-671966.pdf. Accessed 19 Jun 2024"},{"key":"1634_CR10","unstructured":"Regulation - 2016\/429. Regulation - 2016\/429 - EN - EUR-Lex. https:\/\/eur-lex.europa.eu\/eli\/reg\/2016\/429\/oj. Accessed 17 May 2024"},{"key":"1634_CR11","unstructured":"EUROSTAT (2024) Decline in EU livestock population in 2023 - Eurostat. https:\/\/ec.europa.eu\/eurostat\/web\/products-eurostat-news\/w\/ddn-20240521-2. Accessed 23 Jun 2024"},{"key":"1634_CR12","unstructured":"MAPA (2024b) Manual para el control de la infecci\u00f3n por el CMT en establecimientos de ganado caprino incluidos en el Programa Nacional de Erradicacion de la infecci\u00f3n por el complejo Mycobacterium tuberculosis (CMT). https:\/\/www.mapa.gob.es\/es\/ganaderia\/temas\/sanidad-animal-higiene-ganadera\/8manualcaprino2024_tcm30-553693.pdf. Accessed 19 Jun 2024"},{"key":"1634_CR13","doi-asserted-by":"publisher","first-page":"472","DOI":"10.3390\/pathogens9060472","volume":"9","author":"A Balseiro","year":"2020","unstructured":"Balseiro A, Thomas J, Gort\u00e1zar C, Risalde MA (2020) Development and challenges in animal tuberculosis vaccination. Pathogens 9:472","journal-title":"Pathogens"},{"key":"1634_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/s13620-023-00254-9","volume":"76","author":"C Gort\u00e1zar","year":"2023","unstructured":"Gort\u00e1zar C, de la Fuente J, Perell\u00f3 A, Dom\u00ednguez L (2023) Will we ever eradicate animal tuberculosis? Ir Vet J 76:24","journal-title":"Ir Vet J"},{"key":"1634_CR15","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl3962","volume":"383","author":"A Fromsa","year":"2024","unstructured":"Fromsa A, Willgert K, Srinivasan S, Mekonnen G, Bedada W, Gumi B, Lakew M, Tadesse B, Bayissa B, Sirak A, Girma Abdela M, Gebre S, Chibssa T, Veerasami M, Vordermeier HM, Bakker D, Berg S, Ameni G, Juleff N, de Jong MCM, Wood J, Conlan A, Kapur V (2024) BCG vaccination reduces bovine tuberculosis transmission, improving prospects for elimination. Science 383:eadl3962","journal-title":"Science"},{"key":"1634_CR16","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2021.637580","author":"S Srinivasan","year":"2021","unstructured":"Srinivasan S, Conlan AJK, Easterling LA, Herrera C, Dandapat P, Veerasami M, Ameni G, Jindal N, Raj GD, Wood J, Juleff N, Bakker D, Vordermeier M, Kapur V (2021) A meta-analysis of the effect of BacillusCalmette-Gu\u00e9rin vaccination against bovine tuberculosis: is perfect the enemy of good? Front Vet Sci 8:637580","journal-title":"Front Vet Sci"},{"key":"1634_CR17","unstructured":"Balseiro A, Gort\u00e1zar C, S\u00e1ez J L (2024a) Tuberculosis animal: una aproximaci\u00f3n desde la perspectiva de la ciencia y la administraci\u00f3n. https:\/\/www.mapa.gob.es\/es\/ganaderia\/temas\/sanidad-animal-higiene-ganadera\/tbanimalweb_tcm30-553377.pdf. Accessed 19 Jun 2024"},{"key":"1634_CR18","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.tvjl.2017.04.006","volume":"223","author":"J Bezos","year":"2017","unstructured":"Bezos J, Casal C, \u00c1lvarez J, Roy A, Romero B, Rodr\u00edguez-Bertos A, B\u00e1rcena C, D\u00edez A, Juste R, Gort\u00e1zar C, Puentes E, Aguil\u00f3 N, Mart\u00edn C, de Juan L, Dom\u00ednguez L (2017) Evaluation of the Mycobacterium tuberculosis SO2 vaccine using a natural tuberculosis infection model in goats. Vet J 223:60\u201367","journal-title":"Vet J"},{"key":"1634_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s13567-019-0702-7","volume":"50","author":"A Roy","year":"2019","unstructured":"Roy A, Tom\u00e9 I, Romero B, Lorente-Leal V, Infantes-Lorenzo JA, Dom\u00ednguez M, Mart\u00edn C, Aguil\u00f3 N, Puentes E, Rodr\u00edguez E, de Juan L, Risalde MA, Gort\u00e1zar C, Dom\u00ednguez L, Bezos J (2019) Evaluation of the immunogenicity and efficacy of BCG and MTBVAC vaccines using a natural transmission model of tuberculosis. Vet Res 50:82","journal-title":"Vet Res"},{"key":"1634_CR20","doi-asserted-by":"publisher","first-page":"e206","DOI":"10.1111\/j.1863-2378.2010.01329.x","volume":"57","author":"MV Palmer","year":"2010","unstructured":"Palmer MV, Thacker TC, Waters WR, Robbe-Austerman S, Lebepe-Mazur SM, Harris NB (2010) Persistence of Mycobacterium bovis bacillus Calmette-Gu\u00e9rin in white-tailed deer (Odocoileus virginianus) after oral or parenteral vaccination. Zoonoses Public Health 57:e206-212","journal-title":"Zoonoses Public Health"},{"key":"1634_CR21","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nrmicro1419","volume":"4","author":"YAW Skeiky","year":"2006","unstructured":"Skeiky YAW, Sadoff JC (2006) Advances in tuberculosis vaccine strategies. Nat Rev Microbiol 4:469\u2013476","journal-title":"Nat Rev Microbiol"},{"key":"1634_CR22","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s13104-017-2499-7","volume":"10","author":"S Al-Hammadi","year":"2017","unstructured":"Al-Hammadi S, Alsuwaidi AR, Alshamsi ET, Ghatasheh GA, Souid AK (2017) Disseminated Bacillus Calmette-Gu\u00e9rin (BCG) infections in infants with immunodeficiency. BMC Res Notes 10:177","journal-title":"BMC Res Notes"},{"key":"1634_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024905","volume":"6","author":"JM Garrido","year":"2011","unstructured":"Garrido JM, Sevilla IA, Beltr\u00e1n-Beck B, Minguij\u00f3n E, Ballesteros C, Galindo RC, Boadella M, Lyashchenko KP, Romero B, Geijo MV, Ruiz-Fons F, Aranaz A, Juste RA, Vicente J, de la Fuente J, Gort\u00e1zar C (2011) Protection against tuberculosis in Eurasian wild boar vaccinated with heat-inactivated Mycobacterium bovis. PLoS ONE 6:e24905","journal-title":"PLoS ONE"},{"key":"1634_CR24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180546","volume":"12","author":"A Balseiro","year":"2017","unstructured":"Balseiro A, Altuzarra R, Vidal E, Moll X, Espada Y, Sevilla IA, Domingo M, Garrido JM, Juste RA, Prieto M, P\u00e9rez de Val B (2017) Assessment of BCG and inactivated Mycobacterium bovis vaccines in an experimental tuberculosis infection model in sheep. PLoS ONE 12:e0180546","journal-title":"PLoS ONE"},{"key":"1634_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098048","volume":"9","author":"B Beltr\u00e1n-Beck","year":"2014","unstructured":"Beltr\u00e1n-Beck B, de la Fuente J, Garrido JM, Aranaz A, Sevilla I, Villar M, Boadella M, Galindo RC, P\u00e9rez de la Lastra JM, Moreno-Cid JA, Fern\u00e1ndez de Mera IG, Alberdi P, Santos G, Ballesteros C, Lyashchenko KP, Minguij\u00f3n E, Romero B, de Juan L, Dom\u00ednguez L, Juste R, Gortazar C (2014) Oral vaccination with heat inactivated Mycobacterium bovis activates the complement system to protect against tuberculosis. PLoS ONE 9:e98048","journal-title":"PLoS ONE"},{"key":"1634_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2020.00041","volume":"7","author":"A Balseiro","year":"2020","unstructured":"Balseiro A, Prieto JM, \u00c1lvarez V et al (2020) Protective effect of oral BCG and inactivated Mycobacterium bovis vaccines in European badgers (Meles meles) experimentally infected with M. bovis. Front Vet Sci 7:41","journal-title":"Front Vet Sci"},{"key":"1634_CR27","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.vetmic.2017.08.007","volume":"208","author":"J Thomas","year":"2017","unstructured":"Thomas J, Risalde M\u00c1, Serrano M, Sevilla I, Geijo M, Ort\u00edz JA, Fuertes M, Ru\u00edz-Fons JF, de la Fuente J, Dom\u00ednguez L, Juste R, Garrido J, Gort\u00e1zar C (2017) The response of red deer to oral administration of heat-inactivated Mycobacterium bovis and challenge with a field strain. Vet Microbiol 208:195\u2013202","journal-title":"Vet Microbiol"},{"key":"1634_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196948","volume":"13","author":"C Arrieta-Villegas","year":"2018","unstructured":"Arrieta-Villegas C, Per\u00e1lvarez T, Vidal E, Puighibet Z, Moll X, Canturri A, Sevilla IA, Espada Y, Juste RA, Domingo M, P\u00e9rez de Val B (2018) Efficacy of parenteral vaccination against tuberculosis with heat-inactivated Mycobacterium bovis in experimentally challenged goats. PLoS ONE 13:e0196948","journal-title":"PLoS ONE"},{"key":"1634_CR29","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.cimid.2018.09.006","volume":"60","author":"\u00c1 Roy","year":"2018","unstructured":"Roy \u00c1, Risalde MA, Bezos J, Casal C, Romero B, Sevilla I, D\u00edez-Guerrier A, Rodr\u00edguez-Bertos A, Dom\u00ednguez M, Garrido J, Gort\u00e1zar C, Dom\u00ednguez L (2018) Response of goats to intramuscular vaccination with heat-killed Mycobacterium bovis and natural challenge. Comp Immunol Microbiol Infect Dis 60:28\u201334","journal-title":"Comp Immunol Microbiol Infect Dis"},{"key":"1634_CR30","unstructured":"Directive 2010\/63\/UE (2010) Directiva 2010\/63\/UE del Parlamento Europeo y del Consejo, de 22\u00a0de septiembre de 2010, relativa a la protecci\u00f3n de los animales utilizados para fines cient\u00edficos. Texto pertinente a efectos del EEE, OJ L. https:\/\/www.boe.es\/doue\/2010\/276\/L00033-00079.pdf. Accessed 10 Jun 2024"},{"key":"1634_CR31","unstructured":"RD53\/2013 (2013) Real Decreto 53\/2013, de 1 de febrero, por el que se establecen las normas b\u00e1sicas aplicables para la protecci\u00f3n de los animales utilizados en experimentaci\u00f3n y otros fines cient\u00edficos, incluyendo la docencia. https:\/\/www.boe.es\/diario_boe\/txt.php?id=BOE-A-2013-1337. Accessed 10 Jun 2024"},{"key":"1634_CR32","doi-asserted-by":"publisher","DOI":"10.1186\/s13567-022-01047-8","author":"R Vaz-Rodrigues","year":"2022","unstructured":"Vaz-Rodrigues R, Ferreras-Colino E, Ugarte-Ru\u00edz M, Pesciaroli M, Thomas J, Garc\u00eda-Seco T, Sevilla IA, P\u00e9rez-Sancho M, Mateo R, Dom\u00ednguez L, Gortazar C, Risalde MA (2022) Nonspecific protection of heat-inactivated Mycobacterium bovis against Salmonella Choleraesuis infection in pigs. Vet Res 53:31","journal-title":"Vet Res"},{"key":"1634_CR33","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2017.00124","author":"A Roy","year":"2017","unstructured":"Roy A, Risalde MA, Casal C, Romero B, de Juan L, Menshawy AM, D\u00edez-Guerrier A, Juste RA, Garrido JM, Sevilla IA, Gort\u00e1zar C, Dom\u00ednguez L, Bezos J (2017) Oral vaccination with heat-inactivated Mycobacterium bovis does not interfere with the antemortem diagnostic techniques for tuberculosis in goats. Front Vet Sci\u00a04:124","journal-title":"Front Vet Sci"},{"key":"1634_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s12014-017-9171-z","volume":"14","author":"JA Infantes-Lorenzo","year":"2017","unstructured":"Infantes-Lorenzo JA, Moreno I, Risalde ML\u00c1, Roy \u00c1, Villar M, Romero B, Ibarrola N, de la Fuente J, Puentes E, de Juan L, Gort\u00e1zar C, Bezos J, Dom\u00ednguez L, Dom\u00ednguez M (2017) Proteomic characterisation of bovine and avian purified protein derivatives and identification of specific antigens for serodiagnosis of bovine tuberculosis. Clin Proteomics 14:36","journal-title":"Clin Proteomics"},{"key":"1634_CR35","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.jcpa.2005.05.001","volume":"133","author":"A Wangoo","year":"2005","unstructured":"Wangoo A, Johnson L, Gough J, Ackbar R, Inglut S, Hicks D, Spencer Y, Hewinson G, Vordermeier M (2005) Advanced granulomatous lesions in Mycobacterium bovis-infected cattle are associated with increased expression of type I procollagen, gammadelta (WC1+) T cells and CD 68+ cells. J Comp Pathol 133:223\u2013234","journal-title":"J Comp Pathol"},{"key":"1634_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2022.109543","volume":"273","author":"I Agull\u00f3-Ros","year":"2022","unstructured":"Agull\u00f3-Ros I, Andrada M, P\u00e9rez-Sancho M, Roy \u00c1, Bezos J, Bonnet T, Moreno I, Paz-S\u00e1nchez Y, Dom\u00ednguez M, G\u00f3mez-Villamandos JC, Dom\u00ednguez L, Risalde MA (2022) Effect of heat-inactivated Mycobacterium avium subspecies paratuberculosis (MAP) vaccine on the lesions and immunopathology developed in target tissues of naturally MAP-infected goats. Vet Microbiol 273:109543","journal-title":"Vet Microbiol"},{"key":"1634_CR37","unstructured":"R Core Team (2021) R: A Language and environment for statistical computing. (Version 4.1) [Computer software]. https:\/\/cran.r-project.org. Accessed 03 Jun 2024"},{"key":"1634_CR38","unstructured":"Kassambara A, Mundt F (2020) Extract and Visualize the Results of Multivariate Data Analyses [R package factoextra version 1.0.7] https:\/\/www.semanticscholar.org\/author\/A.-Kassambara\/6376218. Accessed 03 Jun 2024."},{"issue":"5","key":"1634_CR39","doi-asserted-by":"publisher","first-page":"e18","DOI":"10.1111\/tbed.12526","volume":"64","author":"I D\u00edez-Delgado","year":"2017","unstructured":"D\u00edez-Delgado I, Rodr\u00edguez O, Boadella M, Garrido JM, Sevilla IA, Bezos J, Juste R, Dom\u00ednguez L, Gort\u00e1zar C (2017) Parenteral vaccination with heat-inactivated Mycobacterium bovis reduces the prevalence of Tuberculosis-compatible lesions in farmed wild boar. Transbound Emerg Dis 64:e18\u2013e21","journal-title":"Transbound Emerg Dis"},{"key":"1634_CR40","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/1746-6148-8-191","volume":"8","author":"B P\u00e9rez de Val","year":"2012","unstructured":"P\u00e9rez de Val B, Nofrar\u00edas M, L\u00f3pez-Soria S, Garrido JM, Vordermeier HM, Villarreal-Ramos B, Mart\u00edn M, Puentes E, Juste RA, Domingo M (2012) Effects of vaccination against paratuberculosis on tuberculosis in goats: diagnostic interferences and cross-protection. BMC Vet Res 8:191","journal-title":"BMC Vet Res"},{"key":"1634_CR41","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.vaccine.2016.01.004","volume":"34","author":"B P\u00e9rez de Val","year":"2016","unstructured":"P\u00e9rez de Val B, Vidal E, L\u00f3pez-Soria S, Marco A, Cervera Z, Mart\u00edn M, Mercader I, Singh M, Raeber A, Domingo M (2016) Assessment of safety and interferon gamma responses of Mycobacterium bovis BCG vaccine in goat kids and milking goats. Vaccine 34:881\u2013886","journal-title":"Vaccine"},{"key":"1634_CR42","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1186\/s12917-017-1182-5","volume":"13","author":"E Vidal","year":"2017","unstructured":"Vidal E, Arrieta-Villegas C, Grasa M, Mercader I, Domingo M, P\u00e9rez de Val B (2017) Field evaluation of the efficacy of Mycobacterium bovis BCG vaccine against tuberculosis in goats. BMC Vet Res 13:252","journal-title":"BMC Vet Res"},{"key":"1634_CR43","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1128\/CVI.00221-14","volume":"21","author":"B Beltr\u00e1n-Beck","year":"2014","unstructured":"Beltr\u00e1n-Beck B, Romero B, Boadella M, Casal C, Bezos J, Mazariegos M, Mart\u00edn M, Galindo RC, P\u00e9rez de la Lastra JM, Villar M, Garrido JM, Sevilla IA, Asensio F, Sicilia J, Lyashchenko KP, Dom\u00ednguez L, Juste RA, de la Fuente J, Gort\u00e1zar C (2014) Tonsils of the soft palate do not mediate the response of pigs to oral vaccination with heat-inactivated Mycobacterium bovis. Clin Vaccine Immunol 21:1128","journal-title":"Clin Vaccine Immunol"},{"key":"1634_CR44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.prevetmed.2018.04.002","volume":"155","author":"I D\u00edez-Delgado","year":"2018","unstructured":"D\u00edez-Delgado I, Sevilla IA, Romero B, Tanner E, Barasona JA, White AR, Lurz PWW, Boots M, de la Fuente J, Dominguez L, Vicente J, Garrido JM, Juste RA, Aranaz A, Gortazar C (2018) Impact of piglet oral vaccination against tuberculosis in endemic free-ranging wild boar populations. Prev Vet Med 155:11\u201320","journal-title":"Prev Vet Med"},{"key":"1634_CR45","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1080\/20477724.2017.1351080","volume":"111","author":"M Faridgohar","year":"2017","unstructured":"Faridgohar M, Nikoueinejad H (2017) New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection. Pathog Glob Health 111:256\u2013264","journal-title":"Pathog Glob Health"},{"key":"1634_CR46","doi-asserted-by":"crossref","unstructured":"Bhat KH, Yaseen I (2018) Mycobacterium tuberculosis: Macrophage takeover and modulation of innate effector responses. In: Mycobacterium: Research and development, Volume 2. InTech.","DOI":"10.5772\/intechopen.75003"},{"key":"1634_CR47","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1111\/tbed.12561","volume":"64","author":"FJ Salguero","year":"2017","unstructured":"Salguero FJ, Gibson S, Garcia-Jimenez W, Gough J, Strickland TS, Vordermeier HM, Villarreal-Ramos B (2017) Differential cell composition and cytokine expression within lymph node granulomas from BCG-vaccinated and non-vaccinated cattle experimentally infected with Mycobacterium bovis. Transbound Emerg Dis 64:1734\u20131749","journal-title":"Transbound Emerg Dis"},{"key":"1634_CR48","doi-asserted-by":"crossref","unstructured":"Sirak A, Tulu B, Bayissa B, Gumi B, Berg S, Salguero FJ, Ameni G, ETHICOBOTS Consortium (2021) Cellular and cytokine responses in lymph node granulomas of Bacillus Calmette Gu\u00e9rin (BCG)-vaccinated and non-vaccinated cross-breed calves naturally infected with Mycobacterium bovis. Front Vet Sci\u00a08:698800","DOI":"10.3389\/fvets.2021.698800"},{"key":"1634_CR49","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.tube.2008.06.003","volume":"88","author":"HC Boddu-Jasmine","year":"2008","unstructured":"Boddu-Jasmine HC, Witchell J, Vordermeier M, Wangoo A, Goyal M (2008) Cytokine mRNA expression in cattle infected with different dosages of Mycobacterium bovis. Tuberculosis 88:610\u2013615","journal-title":"Tuberculosis"},{"key":"1634_CR50","doi-asserted-by":"publisher","first-page":"4620","DOI":"10.4049\/jimmunol.168.9.4620","volume":"168","author":"DR Roach","year":"2002","unstructured":"Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ (2002) TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 168:4620\u20134627","journal-title":"J Immunol"},{"key":"1634_CR51","doi-asserted-by":"publisher","first-page":"13980","DOI":"10.1073\/pnas.0901720106","volume":"106","author":"LJ Abu-Raddad","year":"2009","unstructured":"Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME (2009) Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl Acad Sci U S A 106:13980\u201313985","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1634_CR52","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.smim.2014.04.003","volume":"26","author":"A Dorhoi","year":"2014","unstructured":"Dorhoi A, Kaufmann SHE (2014) Tumor necrosis factor alpha in mycobacterial infection. Semin Immunol 26:203\u2013209","journal-title":"Semin Immunol"},{"key":"1634_CR53","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01298","author":"SJ Yang","year":"2020","unstructured":"Yang SJ, Chen YY, Hsu CH, Hsu CW, Chang CY, Chang JR, Dou HY (2020) Activation of M1 macrophages in response to recombinant TB vaccines with enhanced antimycobacterial activity. Front immunol\u00a011:1298","journal-title":"Front immunol"},{"key":"1634_CR54","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1128\/CVI.00352-10","volume":"18","author":"D Freches","year":"2011","unstructured":"Freches D, Romano M, Korf H, Renauld JC, Van Snick J, Uyttenhove C, Huygen K (2011) Increased pulmonary tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-17A responses compensate for decreased gamma interferon production in anti-IL-12 autovaccine-treated, Mycobacterium bovis BCG-vaccinated mice. Clin Vaccine Immunol 18:95\u2013104","journal-title":"Clin Vaccine Immunol"},{"key":"1634_CR55","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1016\/j.biocel.2012.02.021","volume":"44","author":"RK Dutta","year":"2012","unstructured":"Dutta RK, Kathania M, Raje M, Majumdar S (2012) IL-6 inhibits IFN-\u03b3 induced autophagy in Mycobacterium tuberculosis H37Rv infected macrophages. Int J Biochem Cell Biol 44:942\u2013954","journal-title":"Int J Biochem Cell Biol"},{"key":"1634_CR56","doi-asserted-by":"publisher","first-page":"4750","DOI":"10.4049\/jimmunol.171.9.4750","volume":"171","author":"V Nagabhushanam","year":"2003","unstructured":"Nagabhushanam V, Solache A, Ting LM, Escaron CJ, Zhang JY, Ernst JD (2003) Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol 171:4750\u20134757","journal-title":"J Immunol"},{"key":"1634_CR57","doi-asserted-by":"publisher","first-page":"22132","DOI":"10.1038\/s41598-022-26683-0","volume":"12","author":"C Melgarejo","year":"2022","unstructured":"Melgarejo C, Planas C, Cobos A, Arrieta-Villegas C, Sevilla IA, Bezos J, Moll X, Espada Y, Garrido JM, Domingo M, Vidal E, P\u00e9rez de Val B (2022) A proof-of-concept study to investigate the efficacy of heat-inactivated autovaccines in Mycobacterium caprae experimentally challenged goats. Sci Rep 12:22132","journal-title":"Sci Rep"},{"key":"1634_CR58","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1111\/j.1365-2249.2006.03053.x","volume":"144","author":"S Widdison","year":"2006","unstructured":"Widdison S, Schreuder LJ, Villarreal-Ramos B, Howard CJ, Watson M, Coffey TJ (2006) Cytokine expression profiles of bovine lymph nodes: effects of Mycobacterium bovis infection and bacille Calmette-Gu\u00e9rin vaccination. Clin Exp Immunol 144:281\u2013289","journal-title":"Clin Exp Immunol"},{"key":"1634_CR59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003869","volume":"3","author":"R Jain","year":"2008","unstructured":"Jain R, Dey B, Dhar N, Rao V, Singh R, Gupta UD, Katoch VM, Ramanathan VD, Tyagi AK (2008) Enhanced and enduring protection against tuberculosis by recombinant BCG-Ag85C and its association with modulation of cytokine profile in lung. PLoS One 3:e3869","journal-title":"PLoS ONE"},{"key":"1634_CR60","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11010061","volume":"11","author":"MV Palmer","year":"2022","unstructured":"Palmer MV, Kanipe C, Boggiatto PM (2022) The bovine tuberculoid granuloma. Pathogens 11:61","journal-title":"Pathogens"},{"key":"1634_CR61","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.3390\/ani12233377","volume":"12","author":"F Mili\u00e1n-Suazo","year":"2022","unstructured":"Mili\u00e1n-Suazo F, Gonz\u00e1lez-Ruiz S, Contreras-Magallanes YG, Sosa-Gallegos SL, B\u00e1rcenas-Reyes I, Cant\u00f3-Alarc\u00f3n GJ, Rodr\u00edguez-Hern\u00e1ndez E (2022) Vaccination strategies in a potential use of the vaccine against bovine tuberculosis in infected herds. Animals (Basel) 12:3377","journal-title":"Animals (Basel)"},{"key":"1634_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.prevetmed.2022.105616","volume":"202","author":"R Tschopp","year":"2022","unstructured":"Tschopp R, Zinsstag J, Conlan A, Gemechu G, Wood J, ETHICOBOTS consortium (2022) Productivity loss and cost of bovine tuberculosis for the dairy livestock sector in Ethiopia. Prev Vet Med 202:105616","journal-title":"Prev Vet Med"},{"key":"1634_CR63","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/9780470344538.ch9","volume-title":"Mycobacterium Bovis Infection in Animals and Humans","author":"J Zinsstag","year":"2006","unstructured":"Zinsstag J, Schelling E, Roth F, Kazwala R (2006) Economics of bovine tuberculosis. Mycobacterium Bovis Infection in Animals and Humans, vol 9. Wiley, New York, pp 68\u201383"},{"key":"1634_CR64","doi-asserted-by":"publisher","first-page":"S53","DOI":"10.1016\/j.rvsc.2014.04.015","volume":"97","author":"HM Vordermeier","year":"2014","unstructured":"Vordermeier HM, P\u00e9rez de Val B, Buddle BM, Villarreal-Ramos B, Jones GJ, Hewinson RG, Domingo M (2014) Vaccination of domestic animals against tuberculosis: review of progress and contributions to the field of the TBSTEP project. Res Vet Sci 97:S53-60","journal-title":"Res Vet Sci"}],"container-title":["Veterinary Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13567-025-01634-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13567-025-01634-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13567-025-01634-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T22:27:50Z","timestamp":1762295270000},"score":1,"resource":{"primary":{"URL":"https:\/\/veterinaryresearch.biomedcentral.com\/articles\/10.1186\/s13567-025-01634-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1634"],"URL":"https:\/\/doi.org\/10.1186\/s13567-025-01634-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6762532\/v1","asserted-by":"object"}]},"ISSN":["1297-9716"],"issn-type":[{"value":"1297-9716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"27 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted in accordance with European (Directive 2010\/63\/UE) and Spanish legislation (RD53\/2013). It was approved by the Ethics Committee of the Complutense University of Madrid and the Regional Agriculture Authority of Comunidad de Madrid (permit number: PROEX 143\/15, 29\/06\/2015).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have\u00a0no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"209"}}