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Experimental Infection Models of Tuberculosis in Domestic Livestock

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  • Authors: Bryce M. Buddle1, H. Martin Vordermeier2, R. Glyn Hewinson3
  • Editors: William R. Jacobs Jr.4, Helen McShane5, Valerie Mizrahi6, Ian M. Orme7
    Affiliations: 1: AgResearch, Hopkirk Research Institute, Palmerston North, New Zealand; 2: Animal and Plant Health Agency – Weybridge, Addlestone, Surrey, United Kingdom; 3: AgResearch, Hopkirk Research Institute, Palmerston North, New Zealand; 4: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 5: University of Oxford, Oxford OX3 7DQ, United Kingdom; 6: University of Cape Town, Rondebosch 7701, South Africa; 7: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.TBTB2-0017-2016
  • Received 13 April 2016 Accepted 29 May 2016 Published 26 August 2016
  • B. M. Buddle, [email protected]
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  • Abstract:

    In this article we present experimental infection models in domestic livestock species and how these models were applied to vaccine development, biomarker discovery, and the definition of specific antigens for the differential diagnosis of infected and vaccinated animals. In particular, we highlight synergies between human and bovine tuberculosis (TB) research approaches and data and propose that the application of bovine TB models could make a valuable contribution to human TB vaccine research and that close alignment of both research programs in a one health philosophy will lead to mutual and substantial benefits.

  • Citation: Buddle B, Vordermeier H, Hewinson R. 2016. Experimental Infection Models of Tuberculosis in Domestic Livestock. Microbiol Spectrum 4(4):TBTB2-0017-2016. doi:10.1128/microbiolspec.TBTB2-0017-2016.


1. Waters WR, Palmer MV, Buddle BM, Vordermeier HM. 2012. Bovine tuberculosis vaccine research: historical perspectives and recent advances. Vaccine 30:2611–2622 http://dx.doi.org/10.1016/j.vaccine.2012.02.018. [CrossRef]
2. Daniel R, Evans H, Rolfe S, de la Rua-Domenech R, Crawshaw T, Higgins RJ, Schock A, Clifton-Hadley R. 2009. Outbreak of tuberculosis caused by Mycobacterium bovis in golden Guernsey goats in Great Britain. Vet Rec 165:335–342 http://dx.doi.org/10.1136/vr.165.12.335. [PubMed][CrossRef]
3. More SJ, Cameron AR, Greiner M, Clifton-Hadley RS, Rodeia SC, Bakker D, Salman MD, Sharp JM, De Massis F, Aranaz A, Boniotti MB, Gaffuri A, Have P, Verloo D, Woodford M, Wierup M. 2009. Defining output-based standards to achieve and maintain tuberculosis freedom in farmed deer, with reference to member states of the European Union. Prev Vet Med 90:254–267 http://dx.doi.org/10.1016/j.prevetmed.2009.03.013. [CrossRef]
4. O’Brien DJ, Schmitt SM, Fitzgerald SD, Berry DE, Hickling GJ. 2006. Managing the wildlife reservoir of Mycobacterium bovis: the Michigan, USA, experience. Vet Microbiol 112:313–323 http://dx.doi.org/10.1016/j.vetmic.2005.11.014. [PubMed][CrossRef]
5. Roswurm JD, Ranney AF. 1973. Sharpening the attack on bovine tuberculosis. Am J Public Health 63:884–886 http://dx.doi.org/10.2105/AJPH.63.10.884. [PubMed][CrossRef]
6. Buddle BM, Skinner MA, Wedlock DN, de Lisle GW, Vordermeier HM, Hewinson RG. 2005. Cattle as a model for development of vaccines against human tuberculosis. Tuberculosis (Edinb) 85:19–24 http://dx.doi.org/10.1016/j.tube.2004.09.003. [CrossRef]
7. Waters WR, Palmer MV. 2015. Mycobacterium bovis infection of cattle and white-tailed deer: translational research of relevance to human tuberculosis. ILAR J 56:26–43 http://dx.doi.org/10.1093/ilar/ilv001. [PubMed][CrossRef]
8. Smith NH, Gordon SV, de la Rua-Domenech R, Clifton-Hadley RS, Hewinson RG. 2006. Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis. Nat Rev Microbiol 4:670–681 http://dx.doi.org/10.1038/nrmicro1472. [CrossRef]
9. Berg S, Smith NH. 2014. Why doesn’t bovine tuberculosis transmit between humans? Trends Microbiol 22:552–553 http://dx.doi.org/10.1016/j.tim.2014.08.007. [PubMed][CrossRef]
10. McIlroy SG, Neill SD, McCracken RM. 1986. Pulmonary lesions and Mycobacterium bovis excretion from the respiratory tract of tuberculin reacting cattle. Vet Rec 118:718–721 http://dx.doi.org/10.1136/vr.118.26.718. [PubMed][CrossRef]
11. Liebana E, Johnson L, Gough J, Durr P, Jahans K, Clifton-Hadley R, Spencer Y, Hewinson RG, Downs SH. 2008. Pathology of naturally occurring bovine tuberculosis in England and Wales. Vet J 176:354–360 http://dx.doi.org/10.1016/j.tvjl.2007.07.001. [PubMed][CrossRef]
12. Buddle BM, de Lisle GW, Pfeffer A, Aldwell FE. 1995. Immunological responses and protection against Mycobacterium bovis in calves vaccinated with a low dose of BCG. Vaccine 13:1123–1130 http://dx.doi.org/10.1016/0264-410X(94)00055-R. [CrossRef]
13. Palmer MV, Waters WR, Whipple DL. 2002. Aerosol delivery of virulent Mycobacterium bovis to cattle. Tuberculosis (Edinb) 82:275–282 http://dx.doi.org/10.1054/tube.2002.0341. [PubMed][CrossRef]
14. Rodgers JD, Connery NL, McNair J, Welsh MD, Skuce RA, Bryson DG, McMurray DN, Pollock JM. 2007. Experimental exposure of cattle to a precise aerosolised challenge of Mycobacterium bovis: a novel model to study bovine tuberculosis. Tuberculosis (Edinb) 87:405–414 http://dx.doi.org/10.1016/j.tube.2007.04.003. [CrossRef]
15. Buddle BM, Aldwell FE, Pfeffer A, de Lisle GW, Corner LA. 1994. Experimental Mycobacterium bovis infection of cattle: effect of dose of M. bovis and pregnancy on immune responses and distribution of lesions. N Z Vet J 42:167–172 http://dx.doi.org/10.1080/00480169.1994.35814. [CrossRef]
16. Neill SD, Hanna J, O’Brien JJ, McCracken RM. 1988. Excretion of Mycobacterium bovis by experimentally infected cattle. Vet Rec 123:340–343 http://dx.doi.org/10.1136/vr.123.13.340. [PubMed][CrossRef]
17. Palmer MV, Whipple DL, Rhyan JC, Bolin CA, Saari DA. 1999. Granuloma development in cattle after intratonsilar inoculation with Mycobacterium bovis. Am J Vet Res 60:310–315. [PubMed]
18. Vordermeier HM, Chambers MA, Cockle PJ, Whelan AO, Simmons J, Hewinson RG. 2002. Correlation of ESAT-6-specific gamma interferon production with pathology in cattle following Mycobacterium bovis BCG vaccination against experimental bovine tuberculosis. Infect Immun 70:3026–3032 http://dx.doi.org/10.1128/IAI.70.6.3026-3032.2002. [CrossRef]
19. Wedlock DN, Aldwell FE, Vordermeier HM, Hewinson RG, Buddle BM. 2011. Protection against bovine tuberculosis induced by oral vaccination of cattle with Mycobacterium bovis BCG is not enhanced by co-administration of mycobacterial protein vaccines. Vet Immunol Immunopathol 144:220–227 http://dx.doi.org/10.1016/j.vetimm.2011.09.005. [PubMed][CrossRef]
20. 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, γδ (WC1+) T cells and CD 68+ cells. J Comp Pathol 133:223–234 http://dx.doi.org/10.1016/j.jcpa.2005.05.001. [CrossRef]
21. Waters WR, Palmer MV, Nonnecke BJ, Thacker TC, Scherer CFC, Estes DM, Jacobs WR Jr, Glatman-Freedman A, Larsen MH. 2007. Failure of a Mycobacterium tuberculosis ΔRD1 ΔpanCD double deletion mutant in a neonatal calf aerosol M. bovis challenge model: comparisons to responses elicited by M. bovis bacille Calmette Guerin. Vaccine 25:7832–7840 http://dx.doi.org/10.1016/j.vaccine.2007.08.029. [CrossRef]
22. Ameni G, Vordermeier M, Aseffa A, Young DB, Hewinson RG. 2010. Field evaluation of the efficacy of Mycobacterium bovis bacillus Calmette-Guerin against bovine tuberculosis in neonatal calves in Ethiopia. Clin Vaccine Immunol 17:1533–1538 http://dx.doi.org/10.1128/CVI.00222-10. [CrossRef]
23. Lopez-Valencia G, Renteria-Evangelista T, Williams JJ, Licea-Navarro A, Mora-Valle AL, Medina-Basulto G. 2010. Field evaluation of the protective efficacy of Mycobacterium bovis BCG vaccine against bovine tuberculosis. Res Vet Sci 88:44–49 http://dx.doi.org/10.1016/j.rvsc.2009.05.022.
24. Khatri BL, Coad M, Clifford DJ, Hewinson RG, Whelan AO, Vordermeier HM. 2012. A natural-transmission model of bovine tuberculosis provides novel disease insights. Vet Rec 171:448 http://dx.doi.org/10.1136/vr.101072. [CrossRef]
25. Pesciaroli M, Alvarez J, Boniotti MB, Cagiola M, Di Marco V, Marianelli C, Pacciarini M, Pasquali P. 2014. Tuberculosis in domestic animal species. Res Vet Sci 97(Suppl) :S78–S85 http://dx.doi.org/10.1016/j.rvsc.2014.05.015. [PubMed][CrossRef]
26. Sanchez J, Tomás L, Ortega N, Buendía AJ, del Rio L, Salinas J, Bezos J, Caro MR, Navarro JA. 2011. Microscopical and immunological features of tuberculoid granulomata and cavitary pulmonary tuberculosis in naturally infected goats. J Comp Pathol 145:107–117 http://dx.doi.org/10.1016/j.jcpa.2010.12.006. [CrossRef]
27. Pérez de Val B, López-Soria S, Nofrarías M, Martín M, Vordermeier HM, Villarreal-Ramos B, Romera N, Escobar M, Solanes D, Cardona PJ, Domingo M. 2011. Experimental model of tuberculosis in the domestic goat after endobronchial infection with Mycobacterium caprae. Clin Vaccine Immunol 18:1872–1881 http://dx.doi.org/10.1128/CVI.05323-11. [CrossRef]
28. Gonzalez-Juarrero M, Bosco-Lauth A, Podell B, Soffler C, Brooks E, Izzo A, Sanchez-Campillo J, Bowen R. 2013. Experimental aerosol Mycobacterium bovis model of infection in goats. Tuberculosis (Edinb) 93:558–564 http://dx.doi.org/10.1016/j.tube.2013.05.006. [CrossRef]
29. Bezos J, Casal C, Díez-Delgado I, Romero B, Liandris E, Álvarez J, Sevilla IA, Juan L, Domínguez L, Gortázar C. 2015. Goats challenged with different members of the Mycobacterium tuberculosis complex display different clinical pictures. Vet Immunol Immunopathol 167:185–189 http://dx.doi.org/10.1016/j.vetimm.2015.07.009. [CrossRef]
30. Beatson NS. 1985. Tuberculosis in red deer, p 147–150. In Brown RD (ed), Biology of Deer Production. Springer Verlag, New York.
31. Fitzgerald SD, Kaneene JB. 2013. Wildlife reservoirs of bovine tuberculosis worldwide: hosts, pathology, surveillance, and control. Vet Pathol 50:488–499 http://dx.doi.org/10.1177/0300985812467472. [CrossRef]
32. Griffin JFT, Mackintosh CG, Buchan GS. 1995. Animal models of protective immunity in tuberculosis to evaluate candidate vaccines. Trends Microbiol 3:418–424 http://dx.doi.org/10.1016/S0966-842X(00)88994-5. [CrossRef]
33. Palmer MV, Waters WR, Whipple DL. 2002. Lesion development in white-tailed deer ( Odocoileus virginianus) experimentally infected with Mycobacterium bovis. Vet Pathol 39:334–340 http://dx.doi.org/10.1354/vp.39-3-334. [CrossRef]
34. Buddle BM, Hewinson RG, Vordermeier HM, Wedlock DN. 2013. Subcutaneous administration of a 10-fold lower dose of a human tuberculosis vaccine, Mycobacterium bovis bacille Calmette-Guérin Danish, induced levels of protection against bovine tuberculosis and responses in the tuberculin intradermal test similar to those induced by a standard cattle dose. Clin Vaccine Immunol 20:1559–1562 http://dx.doi.org/10.1128/CVI.00435-13. [CrossRef]
35. Wedlock DN, Aldwell FE, Vordermeier HM, Hewinson RG, Buddle BM. 2011. Protection against bovine tuberculosis induced by oral vaccination of cattle with Mycobacterium bovis BCG is not enhanced by co-administration of mycobacterial protein vaccines. Vet Immunol Immunopathol 144:220–227 http://dx.doi.org/10.1016/j.vetimm.2011.09.005. [PubMed][CrossRef]
36. Dean GS, Clifford D, Whelan AO, Tchilian EZ, Beverley PCL, Salguero FJ, Xing Z, Vordermeier HM, Villarreal-Ramos B. 2015. Protection induced by simultaneous subcutaneous and endobronchial vaccination with BCG/BCG and BCG/adenovirus expressing antigen 85A against Mycobacterium bovis in cattle. PLoS One 10:e0142270. doi:10.1371/journal.pone.0142270 http://dx.doi.org/10.1371/journal.pone.0142270. [CrossRef]
37. Buddle BM, Denis M, Aldwell FE, Vordermeier HM, Hewinson RG, Wedlock DN. 2008. Vaccination of cattle with Mycobacterium bovis BCG by a combination of systemic and oral routes. Tuberculosis (Edinb) 88:595–600 http://dx.doi.org/10.1016/j.tube.2008.01.005. [PubMed][CrossRef]
38. Wedlock DN, Denis M, Vordermeier HM, Hewinson RG, Buddle BM. 2007. Vaccination of cattle with Danish and Pasteur strains of Mycobacterium bovis BCG induce different levels of IFNγ post-vaccination, but induce similar levels of protection against bovine tuberculosis. Vet Immunol Immunopathol 118:50–58 http://dx.doi.org/10.1016/j.vetimm.2007.04.005.
39. Hope JC, Thom ML, McAulay M, Mead E, Vordermeier HM, Clifford D, Hewinson RG, Villarreal-Ramos B. 2011. Identification of surrogates and correlates of protection in protective immunity against Mycobacterium bovis infection induced in neonatal calves by vaccination with M. bovis BCG Pasteur and M. bovis BCG Danish. Clin Vaccine Immunol 18:373–379 http://dx.doi.org/10.1128/CVI.00543-10. [CrossRef]
40. Buddle BM, Wedlock DN, Parlane NA, Corner LA, De Lisle GW, Skinner MA. 2003. Revaccination of neonatal calves with Mycobacterium bovis BCG reduces the level of protection against bovine tuberculosis induced by a single vaccination. Infect Immun 71:6411–6419 http://dx.doi.org/10.1128/IAI.71.11.6411-6419.2003. [CrossRef]
41. Hope JC, Thom ML, Villarreal-Ramos B, Vordermeier HM, Hewinson RG, Howard CJ. 2005. Vaccination of neonatal calves with Mycobacterium bovis BCG induces protection against intranasal challenge with virulent M. bovis.Clin Exp Immunol 139:48–56 http://dx.doi.org/10.1111/j.1365-2249.2005.02668.x. [CrossRef]
42. Thom ML, McAulay M, Vordermeier HM, Clifford D, Hewinson RG, Villarreal-Ramos B, Hope JC. 2012. Duration of immunity against Mycobacterium bovis following neonatal vaccination with bacillus Calmette-Guérin Danish: significant protection against infection at 12, but not 24, months. Clin Vaccine Immunol 19:1254–1260 http://dx.doi.org/10.1128/CVI.00301-12. [CrossRef]
43. Parlane NA, Shu D, Subharat S, Wedlock DN, Rehm BH, de Lisle GW, Buddle BM. 2014. Revaccination of cattle with bacille Calmette-Guérin two years after first vaccination when immunity has waned, boosted protection against challenge with Mycobacterium bovis. PLoS One 9:e106519. doi:10.1371/journal.pone.0106519 http://dx.doi.org/10.1371/journal.pone.0106519. [CrossRef]
44. Pérez de Val B, Villarreal-Ramos B, Nofrarías M, López-Soria S, Romera N, Singh M, Abad FX, Xing Z, Vordermeier HM, Domingo M. 2012. Goats primed with Mycobacterium bovis BCG and boosted with a recombinant adenovirus expressing Ag85A show enhanced protection against tuberculosis. Clin Vaccine Immunol 19:1339–1347 http://dx.doi.org/10.1128/CVI.00275-12. [CrossRef]
45. Pérez de Val B, Vidal E, Villarreal-Ramos B, Gilbert SC, Andaluz A, Moll X, Martín M, Nofrarías M, McShane H, Vordermeier HM, Domingo M. 2013. A multi-antigenic adenoviral-vectored vaccine improves BCG-induced protection of goats against pulmonary tuberculosis infection and prevents disease progression. PLoS One 8:e81317. doi:10.1371/journal.pone.0081317 http://dx.doi.org/10.1371/journal.pone.0081317. [CrossRef]
46. Griffin JF, Mackintosh CG, Rodgers CR. 2006. Factors influencing theprotective efficacy of a BCG homologous prime-boost vaccination regime against tuberculosis. Vaccine 24:835–845 http://dx.doi.org/10.1016/j.vaccine.2005.07.033. [CrossRef]
47. Nol P, Palmer MV, Waters WR, Aldwell FE, Buddle BM, Triantis JM, Linke LM, Phillips GE, Thacker TC, Rhyan JC, Dunbar MR, Salman MD. 2008. Efficacy of oral and parenteral routes of Mycobacterium bovis bacille Calmette-Guerin vaccination against experimental bovine tuberculosis in white-tailed deer ( Odocoileus virginianus): a feasibility study. J Wildl Dis 44:247–259 http://dx.doi.org/10.7589/0090-3558-44.2.247. [CrossRef]
48. Palmer MV, Thacker TC, Waters WR. 2009. Vaccination with Mycobacterium bovis BCG strains Danish and Pasteur in white-tailed deer ( Odocoileus virginianus) experimentally challenged with Mycobacterium bovis. Zoonoses Public Health 56:243–251 http://dx.doi.org/10.1111/j.1863-2378.2008.01198.x. [CrossRef]
49. Palmer MV, Thacker TC, Waters WR, Robbe-Austerman S, Lebepe-Mazur SM, Harris NB. 2010. Persistence of Mycobacterium bovis bacillus Calmette-Guérin in white-tailed deer ( Odocoileus virginianus) after oral or parenteral vaccination. Zoonoses Public Health 57:e206–e212 http://dx.doi.org/10.1111/j.1863-2378.2010.01329.x. [CrossRef]
50. Nol P, Rhyan JC, Robbe-Austerman S, McCollum MP, Rigg TD, Saklou NT, Salman MD. 2013. The potential for transmission of BCG from orally vaccinated white-tailed deer ( Odocoileus virginianus) to cattle ( Bos taurus) through a contaminated environment: experimental findings. PLoS One 8:e60257. doi:10.1371/journal.pone.0060257 http://dx.doi.org/10.1371/journal.pone.0060257. [CrossRef]
51. Rizzi C, Bianco MV, Blanco FC, Soria M, Gravisaco MJ, Montenegro V, Vagnoni L, Buddle B, Garbaccio S, Delgado F, Leal KS, Cataldi AA, Dellagostin OA, Bigi F. 2012. Vaccination with a BCG strain overexpressing Ag85B protects cattle against Mycobacterium bovis challenge. PLoS One 7:e51396. doi:10.1371/journal.pone.0051396 http://dx.doi.org/10.1371/journal.pone.0051396. [CrossRef]
52. Khatri B, Whelan A, Clifford D, Petrera A, Sander P, Vordermeier HM. 2014. BCG Δzmp1 vaccine induces enhanced antigen specific immune responses in cattle. Vaccine 32:779–784 http://dx.doi.org/10.1016/j.vaccine.2013.12.055. [CrossRef]
53. Grode L, Ganoza CA, Brohm C, Weiner J III, Eisele B, Kaufmann SH. 2013. Safety and immunogenicity of the recombinant BCG vaccine VPM1002 in a phase 1 open-label randomized clinical trial. Vaccine 31:1340–1348 http://dx.doi.org/10.1016/j.vaccine.2012.12.053. [PubMed][CrossRef]
54. Grode L, Seiler P, Baumann S, Hess J, Brinkmann V, Nasser Eddine A, Mann P, Goosmann C, Bandermann S, Smith D, Bancroft GJ, Reyrat JM, van Soolingen D, Raupach B, Kaufmann SH. 2005. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin. J Clin Invest 115:2472–2479 http://dx.doi.org/10.1172/JCI24617. [CrossRef]
55. Waters WR, Maggioli MF, Palmer MV, Thacker TC, McGill JL, Vordermeier HM, Berney-Meyer L, Jacobs WR Jr, Larsen MH. 2016. Interleukin-17A as a biomarker for bovine tuberculosis. Clin Vaccine Immunol 23:168–180 http://dx.doi.org/10.1128/CVI.00637-15. [PubMed][CrossRef]
56. Buddle BM, Wards BJ, Aldwell FE, Collins DM, de Lisle GW. 2002. Influence of sensitisation to environmental mycobacteria on subsequent vaccination against bovine tuberculosis. Vaccine 20:1126–1133 http://dx.doi.org/10.1016/S0264-410X(01)00436-4. [CrossRef]
57. Khare S, Hondalus MK, Nunes J, Bloom BR, Adams LG. 2007. Mycobacterium bovis ΔleuD auxotroph-induced protective immunity against tissue colonization, burden and distribution in cattle intranasally challenged with Mycobacterium bovis Ravenel S. Vaccine 25:1743–1755 http://dx.doi.org/10.1016/j.vaccine.2006.11.036. [CrossRef]
58. Waters WR, Palmer MV, Nonnecke BJ, Thacker TC, Scherer CFC, Estes DM, Hewinson RG, Vordermeier HM, Barnes SW, Federe GC, Walker JR, Glynne RJ, Hsu T, Weinrick B, Biermann K, Larsen MH, Jacobs WR Jr. 2009. Efficacy and immunogenicity of Mycobacterium bovis ΔRD1 against aerosol M. bovis infection in neonatal calves. Vaccine 27:1201–1209 http://dx.doi.org/10.1016/j.vaccine.2008.12.018. [PubMed][CrossRef]
59. Blanco FC, Bianco MV, Garbaccio S, Meikle V, Gravisaco MJ, Montenegro V, Alfonseca E, Singh M, Barandiaran S, Canal A, Vagnoni L, Buddle BM, Bigi F, Cataldi A. 2013. Mycobacterium bovis Δmce2 double deletion mutant protects cattle against challenge with virulent M. bovis. Tuberculosis (Edinb) 93:363–372 http://dx.doi.org/10.1016/j.tube.2013.02.004. [CrossRef]
60. Maue AC, Waters WR, Palmer MV, Whipple DL, Minion FC, Brown WC, Estes DM. 2004. CD80 and CD86, but not CD154, augment DNA vaccine-induced protection in experimental bovine tuberculosis. Vaccine 23:769–779 http://dx.doi.org/10.1016/j.vaccine.2004.07.019. [PubMed][CrossRef]
61. Cai H, Tian X, Hu XD, Li SX, Yu DH, Zhu YX. 2005. Combined DNA vaccines formulated either in DDA or in saline protect cattle from Mycobacterium bovis infection. Vaccine 23:3887–3895 http://dx.doi.org/10.1016/j.vaccine.2005.03.025. [CrossRef]
62. Skinner MA, Buddle BM, Wedlock DN, Keen D, de Lisle GW, Tascon RE, Ferraz JC, Lowrie DB, Cockle PJ, Vordermeier HM, Hewinson RG. 2003. A DNA prime- Mycobacterium bovis BCG boost vaccination strategy for cattle induces protection against bovine tuberculosis. Infect Immun 71:4901–4907 http://dx.doi.org/10.1128/IAI.71.9.4901-4907.2003. [CrossRef]
63. Skinner MA, Wedlock DN, de Lisle GW, Cooke MM, Tascon RE, Ferraz JC, Lowrie DB, Vordermeier HM, Hewinson RG, Buddle BM. 2005. The order of prime-boost vaccination of neonatal calves with Mycobacterium bovis BCG and a DNA vaccine encoding mycobacterial proteins Hsp65, Hsp70, and Apa is not critical for enhancing protection against bovine tuberculosis. Infect Immun 73:4441–4444 http://dx.doi.org/10.1128/IAI.73.7.4441-4444.2005. [CrossRef]
64. Maue AC, Waters WR, Palmer MV, Nonnecke BJ, Minion FC, Brown WC, Norimine J, Foote MR, Scherer CF, Estes DM. 2007. An ESAT-6:CFP10 DNA vaccine administered in conjunction with Mycobacterium bovis BCG confers protection to cattle challenged with virulent M. bovis. Vaccine 25:4735–4746 http://dx.doi.org/10.1016/j.vaccine.2007.03.052. [CrossRef]
65. Wedlock DN, Denis M, Skinner MA, Koach J, de Lisle GW, Vordermeier HM, Hewinson RG, van Drunen Littel-van den Hurk S, Babiuk LA, Hecker R, Buddle BM. 2005. Vaccination of cattle with a CpG oligodeoxynucleotide-formulated mycobacterial protein vaccine and Mycobacterium bovis BCG induces levels of protection against bovine tuberculosis superior to those induced by vaccination with BCG alone. Infect Immun 73:3540–3546 http://dx.doi.org/10.1128/IAI.73.6.3540-3546.2005. [CrossRef]
66. Wedlock DN, Denis M, Painter GF, Ainge GD, Vordermeier HM, Hewinson RG, Buddle BM. 2008. Enhanced protection against bovine tuberculosis after coadministration of Mycobacterium bovis BCG with a mycobacterial protein vaccine-adjuvant combination but not after coadministration of adjuvant alone. Clin Vaccine Immunol 15:765–772 http://dx.doi.org/10.1128/CVI.00034-08. [PubMed][CrossRef]
67. Vordermeier HM, Villarreal-Ramos B, Cockle PJ, McAulay M, Rhodes SG, Thacker T, Gilbert SC, McShane H, Hill AV, Xing Z, Hewinson RG. 2009. Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis. Infect Immun 77:3364–3373 http://dx.doi.org/10.1128/IAI.00287-09. [CrossRef]
68. Dean G, Whelan A, Clifford D, Salguero FJ, Xing Z, Gilbert S, McShane H, Hewinson RG, Vordermeier M, Villarreal-Ramos B. 2014. Comparison of the immunogenicity and protection against bovine tuberculosis following immunization by BCG-priming and boosting with adenovirus or protein based vaccines. Vaccine 32:1304–1310 http://dx.doi.org/10.1016/j.vaccine.2013.11.045. [CrossRef]
69. Dean G, Clifford D, Gilbert S, McShane H, Hewinson RG, Vordermeier HM, Villarreal-Ramos B. 2014. Effect of dose and route of immunisation on the immune response induced in cattle by heterologous Bacille Calmette-Guerin priming and recombinant adenoviral vector boosting. Vet Immunol Immunopathol 158:208–213 http://dx.doi.org/10.1016/j.vetimm.2014.01.010. [CrossRef]
70. Whelan A, Court P, Xing Z, Clifford D, Hogarth PJ, Vordermeier M, Villarreal-Ramos B. 2012. Immunogenicity comparison of the intradermal or endobronchial boosting of BCG vaccinates with Ad5-85A. Vaccine 30:6294–6300 http://dx.doi.org/10.1016/j.vaccine.2012.07.086. [PubMed][CrossRef]
71. Satti I, Meyer J, Harris SA, Manjaly Thomas ZR, Griffiths K, Antrobus RD, Rowland R, Ramon RL, Smith M, Sheehan S, Bettinson H, McShane H. 2014. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial. Lancet Infect Dis 14:939–946 http://dx.doi.org/10.1016/S1473-3099(14)70845-X. [CrossRef]
72. Vordermeier HM, Huygen K, Singh M, Hewinson RG, Xing Z. 2006. Immune responses induced in cattle by vaccination with a recombinant adenovirus expressing mycobacterial antigen 85A and Mycobacterium bovis BCG. Infect Immun 74:1416–1418 http://dx.doi.org/10.1128/IAI.74.2.1416-1418.2006.
73. Blunt L, Hogarth PJ, Kaveh DA, Webb P, Villarreal-Ramos B, Vordermeier HM. 2015. Phenotypic characterization of bovine memory cells responding to mycobacteria in IFNγ enzyme linked immunospot assays. Vaccine 33:7276–7282 http://dx.doi.org/10.1016/j.vaccine.2015.10.113. [CrossRef]
74. Maggioli MF, Palmer MV, Thacker TC, Vordermeier HM, Waters WR. 2015. Characterization of effector and memory T cell subsets in the immune response to bovine tuberculosis in cattle. PLoS One 10:e0122571. doi:10.1371/journal.pone.0122571. http://dx.doi.org/10.1371/journal.pone.0122571. [PubMed][CrossRef]
75. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, Locksley RM, Haynes L, Randall TD, Cooper AM. 2007. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8:369–377 http://dx.doi.org/10.1038/ni1449. [CrossRef]
76. Khader SA, Cooper AM. 2008. IL-23 and IL-17 in tuberculosis. Cytokine 41:79–83 http://dx.doi.org/10.1016/j.cyto.2007.11.022. [CrossRef]
77. Bhuju S, Aranday-Cortes E, Villarreal-Ramos B, Xing Z, Singh M, Vordermeier HM. 2012. Global gene transcriptome analysis in vaccinated cattle revealed a dominant role of IL-22 for protection against bovine tuberculosis. PLoS Pathog 8:e1003077. doi:10.1371/journal.ppat.1003077 http://dx.doi.org/10.1371/journal.ppat.1003077.
78. Aagaard C, Hoang TT, Izzo A, Billeskov R, Troudt J, Arnett K, Keyser A, Elvang T, Andersen P, Dietrich J. 2009. Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose. PLoS One 4:e5930. doi:10.1371/journal.pone.0005930 http://dx.doi.org/10.1371/journal.pone.0005930. [CrossRef]
79. McShane H. 2009. Vaccine strategies against tuberculosis. Swiss Med Wkly 139:156–160. [PubMed]
80. Nambiar JK, Pinto R, Aguilo JI, Takatsu K, Martin C, Britton WJ, Triccas JA. 2012. Protective immunity afforded by attenuated, PhoP-deficient Mycobacterium tuberculosis is associated with sustained generation of CD4+ T-cell memory. Eur J Immunol 42:385–392 http://dx.doi.org/10.1002/eji.201141903. [CrossRef]
81. Whelan AO, Villarreal-Ramos B, Vordermeier HM, Hogarth PJ. 2011. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM) cells in cattle naturally infected with bovine tuberculosis. PLoS One 6:e29194. doi:10.1371/journal.pone.0029194 http://dx.doi.org/10.1371/journal.pone.0029194. [CrossRef]
82. Geiger R, Duhen T, Lanzavecchia A, Sallusto F. 2009. Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J Exp Med 206:1525–1534 http://dx.doi.org/10.1084/jem.20090504. [CrossRef]
83. Patke DS, Farber DL. 2005. Modulation of memory CD4 T cell function and survival potential by altering the strength of the recall stimulus. J Immunol 174:5433–5443 http://dx.doi.org/10.4049/jimmunol.174.9.5433. [PubMed][CrossRef]
84. Caserta S, Kleczkowska J, Mondino A, Zamoyska R. 2010. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J Immunol 185:6545–6554 http://dx.doi.org/10.4049/jimmunol.1001867. [PubMed][CrossRef]
85. Vordermeier HM, Rhodes SG, Dean G, Goonetilleke N, Huygen K, Hill AV, Hewinson RG, Gilbert SC. 2004. Cellular immune responses induced in cattle by heterologous prime-boost vaccination using recombinant viruses and bacille Calmette-Guérin. Immunology 112:461–470 http://dx.doi.org/10.1111/j.1365-2567.2004.01903.x. [CrossRef]
86. Golby P, Villarreal-Ramos B, Dean G, Jones GJ, Vordermeier M. 2014. MicroRNA expression profiling of PPD-B stimulated PBMC from M. bovis-challenged unvaccinated and BCG vaccinated cattle. Vaccine 32:5839–5844 http://dx.doi.org/10.1016/j.vaccine.2014.07.034. [CrossRef]
87. Huang J, Jiao J, Xu W, Zhao H, Zhang C, Shi Y, Xiao Z. 2015. MiR-155 is up-regulated in patients with active tuberculosis and inhibits apoptosis of monocytes by targeting FOXO3. Mol Med Rep 12:7102–7108. [PubMed]
88. Aranday-Cortes E, Hogarth PJ, Kaveh DA, Whelan AO, Villarreal-Ramos B, Lalvani A, Vordermeier HM. 2012. Transcriptional profiling of disease-induced host responses in bovine tuberculosis and the identification of potential diagnostic biomarkers. PLoS One 7:e30626. http://dx.doi.org/10.1371/journal.pone.0030626. [CrossRef]
89. Ruhwald M, Aabye MG, Ravn P. 2012. IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions. Expert Rev Mol Diagn 12:175–187 http://dx.doi.org/10.1586/erm.11.97. [PubMed][CrossRef]
90. Berggren SA. 1981. Field experiment with BCG vaccine in Malawi. Br Vet J 137:88–96. [PubMed]
91. Buddle BM, Parlane NA, Keen DL, Aldwell FE, Pollock JM, Lightbody K, Andersen P. 1999. Differentiation between Mycobacterium bovis BCG-vaccinated and M. bovis-infected cattle by using recombinant mycobacterial antigens. Clin Diagn Lab Immunol 6:1–5. [PubMed]
92. Vordermeier HM, Cockle PC, Whelan A, Rhodes S, Palmer N, Bakker D, Hewinson RG. 1999. Development of diagnostic reagents to differentiate between Mycobacterium bovis BCG vaccination and M. bovis infection in cattle. Clin Diagn Lab Immunol 6:675–682. [PubMed]
93. Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, Pryor M, Duthoy S, Grondin S, Lacroix C, Monsempe C, Simon S, Harris B, Atkin R, Doggett J, Mayes R, Keating L, Wheeler PR, Parkhill J, Barrell BG, Cole ST, Gordon SV, Hewinson RG. 2003. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci USA 100:7877–7882 http://dx.doi.org/10.1073/pnas.1130426100. [CrossRef]
94. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE III, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 http://dx.doi.org/10.1038/31159. [CrossRef]
95. Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, Valenti P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST. 2007. Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci USA 104:5596–5601 http://dx.doi.org/10.1073/pnas.0700869104. [PubMed][CrossRef]
96. Li L, Bannantine JP, Zhang Q, Amonsin A, May BJ, Alt D, Banerji N, Kanjilal S, Kapur V. 2005. The complete genome sequence of Mycobacterium avium subspecies paratuberculosis. Proc Natl Acad Sci USA 102:12344–12349 http://dx.doi.org/10.1073/pnas.0505662102. [CrossRef]
97. Mustafa AS, Cockle PJ, Shaban F, Hewinson RG, Vordermeier HM. 2002. Immunogenicity of Mycobacterium tuberculosis RD1 region gene products in infected cattle. Clin Exp Immunol 130:37–42 http://dx.doi.org/10.1046/j.1365-2249.2002.01937.x. [PubMed][CrossRef]
98. Wilkinson KA, Stewart GR, Newton SM, Vordermeier HM, Wain JR, Murphy HN, Horner K, Young DB, Wilkinson RJ. 2005. Infection biology of a novel alpha-crystallin of Mycobacterium tuberculosis: Acr2. J Immunol 174:4237–4243 http://dx.doi.org/10.4049/jimmunol.174.7.4237. [PubMed][CrossRef]
99. Mustafa AS, Skeiky YA, Al-Attiyah R, Alderson MR, Hewinson RG, Vordermeier HM. 2006. Immunogenicity of Mycobacterium tuberculosis antigens in Mycobacterium bovis BCG-vaccinated and M. bovis-infected cattle. Infect Immun 74:4566–4572 http://dx.doi.org/10.1128/IAI.01660-05. [CrossRef]
100. Jones GJ, Pirson C, Gideon HP, Wilkinson KA, Sherman DR, Wilkinson RJ, Hewinson RG, Vordermeier HM. 2011. Immune responses to the enduring hypoxic response antigen Rv0188 are preferentially detected in Mycobacterium bovis infected cattle with low pathology. PLoS One 6:e21371. doi:10.1371/journal.pone.0021371 http://dx.doi.org/10.1371/journal.pone.0021371. [CrossRef]
101. Gideon HP, Wilkinson KA, Rustad TR, Oni T, Guio H, Sherman DR, Vordermeier HM, Robertson BD, Young DB, Wilkinson RJ. 2012.Bioinformatic and empirical analysis of novel hypoxia-inducible targets of the human antituberculosis T cell response. J Immunol 189:5867–5876 http://dx.doi.org/10.4049/jimmunol.1202281. [CrossRef]
102. Vordermeier HM, Hewinson RG, Wilkinson RJ, Wilkinson KA, Gideon HP, Young DB, Sampson SL. 2012. Conserved immune recognition hierarchy of mycobacterial PE/PPE proteins during infection in natural hosts. PLoS One 7:e40890. doi:10.1371/journal.pone.0040890 http://dx.doi.org/10.1371/journal.pone.0040890. [CrossRef]
103. Pollock JM, Andersen P. 1997. The potential of the ESAT-6 antigen secreted by virulent mycobacteria for specific diagnosis of tuberculosis. J Infect Dis 175:1251–1254 http://dx.doi.org/10.1086/593686. [PubMed][CrossRef]
104. Vordermeier HM, Whelan A, Cockle PJ, Farrant L, Palmer N, Hewinson RG. 2001. Use of synthetic peptides derived from the antigens ESAT-6 and CFP-10 for differential diagnosis of bovine tuberculosis in cattle. Clin Diagn Lab Immunol 8:571–578. [PubMed][CrossRef]
105. Buddle BM, Ryan TJ, Pollock JM, Andersen P, de Lisle GW. 2001. Use of ESAT-6 in the interferon-γ test for diagnosis of bovine tuberculosis following skin testing. Vet Microbiol 80:37–46 http://dx.doi.org/10.1016/S0378-1135(00)00375-8. [PubMed][CrossRef]
106. Sidders B, Withers M, Kendall SL, Bacon J, Waddell SJ, Hinds J, Golby P, Movahedzadeh F, Cox RA, Frita R, Ten Bokum AM, Wernisch L, Stoker NG. 2007. Quantification of global transcription patterns in prokaryotes using spotted microarrays. Genome Biol 8:R265. http://dx.doi.org/10.1186/gb-2007-8-12-r265. [CrossRef]
107. Millington KA, Fortune SM, Low J, Garces A, Hingley-Wilson SM, Wickremasinghe M, Kon OM, Lalvani A. 2011. Rv3615c is a highly immunodominant RD1 (region of difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 108:5730–5735 http://dx.doi.org/10.1073/pnas.1015153108. [CrossRef]
108. Pollock JM, Andersen P. 1997. Predominant recognition of the ESAT-6 protein in the first phase of infection with Mycobacterium bovis in cattle. Infect Immun 65:2587–2592. [PubMed]
109. Ravn P, Demissie A, Eguale T, Wondwosson H, Lein D, Amoudy HA, Mustafa AS, Jensen AK, Holm A, Rosenkrands I, Oftung F, Olobo J, von Reyn F, Andersen P. 1999. Human T cell responses to the ESAT-6 antigen from Mycobacterium tuberculosis. J Infect Dis 179:637–645 http://dx.doi.org/10.1086/314640. [PubMed][CrossRef]
110. van Pinxteren LA, Ravn P, Agger EM, Pollock J, Andersen P. 2000. Diagnosis of tuberculosis based on the two specific antigens ESAT-6 and CFP10. Clin Diagn Lab Immunol 7:155–160. [PubMed][CrossRef]
111. Cockle PJ, Gordon SV, Lalvani A, Buddle BM, Hewinson RG, Vordermeier HM. 2002. Identification of novel Mycobacterium tuberculosis antigens with potential as diagnostic reagents or subunit vaccine candidates by comparative genomics. Infect Immun 70:6996–7003 http://dx.doi.org/10.1128/IAI.70.12.6996-7003.2002. [CrossRef]
112. Cockle PJ, Gordon SV, Hewinson RG, Vordermeier HM. 2006. Field evaluation of a novel differential diagnostic reagent for detection of Mycobacterium bovis in cattle. Clin Vaccine Immunol 13:1119–1124 http://dx.doi.org/10.1128/CVI.00209-06. [PubMed][CrossRef]
113. Sidders B, Pirson C, Hogarth PJ, Hewinson RG, Stoker NG, Vordermeier HM, Ewer K. 2008. Screening of highly expressed mycobacterial genes identifies Rv3615c as a useful differential diagnostic antigen for the Mycobacterium tuberculosis complex. Infect Immun 76:3932–3939 http://dx.doi.org/10.1128/IAI.00150-08. [CrossRef]
114. Jones GJ, Gordon SV, Hewinson RG, Vordermeier HM. 2010. Screening of predicted secreted antigens from Mycobacterium bovis reveals the immunodominance of the ESAT-6 protein family. Infect Immun 78:1326–1332 http://dx.doi.org/10.1128/IAI.01246-09. [PubMed][CrossRef]
115. Jones GJ, Hewinson RG, Vordermeier HM. 2010. Screening of predicted secreted antigens from Mycobacterium bovis identifies potential novel differential diagnostic reagents. Clin Vaccine Immunol 17:1344–1348 http://dx.doi.org/10.1128/CVI.00261-10. [CrossRef]
116. Lindestam Arlehamn CS, Gerasimova A, Mele F, Henderson R, Swann J, Greenbaum JA, Kim Y, Sidney J, James EA, Taplitz R, McKinney DM, Kwok WW, Grey H, Sallusto F, Peters B, Sette A. 2013. Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset. PLoS Pathog 9:e1003130. doi:10.1371/journal.ppat.1003130 http://dx.doi.org/10.1371/journal.ppat.1003130.
117. Whelan AO, Clifford D, Upadhyay B, Breadon EL, McNair J, Hewinson GR, Vordermeier MH. 2010. Development of a skin test for bovine tuberculosis for differentiating infected from vaccinated animals. J Clin Microbiol 48:3176–3181 http://dx.doi.org/10.1128/JCM.00420-10. [PubMed][CrossRef]
118. Parlane NA, Chen S, Jones GJ, Vordermeier HM, Wedlock DN, Rehm BHA, Buddle BM. 2015. Display of antigens on polyester inclusions lowers the antigen concentration required for a bovine tuberculosis skin test. Clin Vaccine Immunol 23:19–26 http://dx.doi.org/10.1128/CVI.00462-15. [CrossRef]
119. Arend SM, Franken WP, Aggerbeck H, Prins C, van Dissel JT, Thierry-Carstensen B, Tingskov PN, Weldingh K, Andersen P. 2008. Double-blind randomized phase I study comparing rdESAT-6 to tuberculin as skin test reagent in the diagnosis of tuberculosis infection. Tuberculosis (Edinb) 88:249–261 http://dx.doi.org/10.1016/j.tube.2007.11.004. [CrossRef]

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In this article we present experimental infection models in domestic livestock species and how these models were applied to vaccine development, biomarker discovery, and the definition of specific antigens for the differential diagnosis of infected and vaccinated animals. In particular, we highlight synergies between human and bovine tuberculosis (TB) research approaches and data and propose that the application of bovine TB models could make a valuable contribution to human TB vaccine research and that close alignment of both research programs in a one health philosophy will lead to mutual and substantial benefits.

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Use of cattle as a model of TB in humans

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.TBTB2-0017-2016
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Types of new TB vaccines tested in cattle

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.TBTB2-0017-2016
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Potential correlates of protection defined in cattle

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.TBTB2-0017-2016

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