Inmunogenicidad del antígeno ESAT-6 de Mycobacterium tuberculosis en monos búho
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Calderon, M., Parra-López, C., Alfonso, R., Barato, P., Giraldo, D., Pinto, M., & Patarroyo, M. (2006). Inmunogenicidad del antígeno ESAT-6 de Mycobacterium tuberculosis en monos búho. NOVA, 4(5). https://doi.org/10.22490/24629448.344
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Martha Calderon
Carlos Parra-López
Rosalba Alfonso
Paola Barato
Diana Giraldo
Martha Pinto
Manuel Patarroyo
Resumen
La ̇única vacuna disponible contra la tuberculosis es la cepaMycobacterium bovisBCG, que ofrece unaeficacia protectiva variable (0%-80%), siendo urgente un nuevo agente profil·ctico. Se han evaluado diversos candidatos a vacuna contra este patogeno, en los modelos animales de experimentaciÛn convencionales(murino, cobayo, conejo), obteniÈndose informaciÛn b·sica sobre el efecto de la vacuna en la carga bacterialfrente a un reto infeccioso, asÌ como tambiÈn la reducciÛn o prevenciÛn de la patologÌa en los pulmones uotros Ûrganos blanco; adem·s de los aspectos relacionados con la respuesta inmune hacia elMycobacteriumtuberculosis. Los primates no humanos tienen ventajas sobre los modelos convencionales en la evaluaciÛn devacunas, de hecho se ha verificado el comportamiento de agentes terapÈuticos en humanos despuÈs de habersido medida la capacidad protectiva de Èstos en monos con tuberculosis inducida. Los primates mas estudia-dos en la infección por micobacterias son el cynomulgus, y el rhesus, observ·ndose que estos animalesmantienen la infección en un estado subclÌnico, muy similar a la tuberculosis humana donde el 90% de lapoblación infectada mantiene la infecciÛn en un estado latente. Dado que el modelo animal debe semejar el comportamiento de las proteÌnas estudiadas en el ser humano, el monoAotuspuede representar ventajas enla investigación de tuberculosis por ser un primate con aproximadamente un 90% de similitud al humano encuanto a las molÈculas del sistema inmune estudiadas hasta hoy. La proteÌna ESAT-6 de (early secretoryantigenic target 6 kD) deMycobacterium tuberculosises un componente minoritario del filtrado de cultivode corto tiempo (CFP), ha sido genÈtica y quÌmicamente caracterizada e induce una potente respuestainmunogÈnica del tipo TH1. Este antÌgeno es secretado durante la fase inicial de crecimiento siendo fuerte-mente reconocido por animales y humanos infectados porMycobacterium tuberculosis, este hecho haceque su inclusiÛn en una futura vacuna anti-tuberculosis por subunidades y en pruebas de inmunodiagnÛstico.En este trabajo se estudiÛ la respuesta inmune del monoAotusfrente al antÌgeno micobacteriano ESAT-6 enforma recombinante (rESAT-6). El antÌgeno fue inmunizado junto con el adyuvante Montanide 720 producien-do una fuerte respuesta humoral y celular, no solo hacia rESAT-6 sino tambiÈn hacia la proteÌna nativa pre-sente en el filtrado de medio de cultivo deMycobacterium tuberculosis.La respuesta celular fue medidapor la incorporaciÛn de [3H]timidina en ensayos de linfoproliferaciÛn. La respuesta humoral se analizÛ porensayos de ELISA e inmunoblot, obteniÈndose altos tÌtulos de anticuerpos (hasta de 1:12,800) dirigidos rESAT-6. Se demostrÛ la naturaleza multiepitope de este antÌgeno ya que en general pÈptidos que mapean la proteÌnafueron especÌficamente reconocidos tanto a nivel celular como humoral. Se observÛ adem·s variaciÛn en larespuesta a la vacunación entre animal y animal, siendo una desventaja para un modelo de experimentación en cuanto a la predicción de la respuesta. Este estudio se constituye en un primer paso de evaluaciÛn delmonoAotuscomo modelo animal en tuberculosis.
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DOI: http://dx.doi.org/10.22490/24629448.344
2. Fine PE: Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346:1339-1345, 1995
3. Ginsberg AM: What.s new in tuberculosis vaccines? Bull World Health Organ 80:483-488, 2002
4 . Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, 3rd, 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, Barrell BG, et al.: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537-544, 1998
5 . Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST: Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber Lung Dis 79:329-342, 1999
6 . Jungblut PR, Schaible UE, Mollenkopf HJ, Zimny-Arndt U, Raupach B, Mattow J, Halada P, Lamer S, Hagens K, Kaufmann SH: Comparative proteome analysis of Mycobacterium tuberculosis and Mycobacterium bovis BCG strains: towards functional genomics of microbial pathogens. Mol Microbiol 33:1103-1117, 1999
7 . Domenech P, Barry CE, 3rd, Cole ST: Mycobacterium tuberculosis in the post-genomic age. Curr Opin Microbiol 4:28-34, 2001
8. Covert BA, Spencer JS, Orme IM, Belisle JT: The application of proteomics in defining the T cell antigens of Mycobacterium tuberculosis. Proteomics 1:574-586, 2001
9 Brennan PJ: Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberculosis (Edinb) 83:91-97, 2003
10. Brennan PJ, Besra GS: Structure, function and biogenesis of the mycobacterial cell wall. Biochem Soc Trans 25:188-194, 1997
11. Orme IM, Cooper AM: Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 20:307-312, 1999
12. Flynn JL, Chan J: Immunology of tuberculosis. Annu Rev Immunol 19:93-129, 2001
13. Pym AS, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A, Griffiths KE, Marchal G, Leclerc C, Cole ST: Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 9:533-539, 2003
14. Bao L, Chen W, Zhang H, Wang X: Virulence, immunogenicity, and protective efficacy of two recombinant Mycobacterium bovis bacillus Calmette-Guerin strains expressing the antigen ESAT-6 from Mycobacterium tuberculosis. Infect Immun 71:1656-1661, 2003
15. Jackson M, Phalen SW, Lagranderie M, Ensergueix D, Chavarot P, Marchal G, McMurray DN, Gicquel B, Guilhot C: Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine. Infect Immun 67:2867-2873, 1999
16. Kamath AT, Feng CG, Macdonald M, Briscoe H, Britton WJ: Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis. Infect Immun 67:1702-1707, 1999
17. Li Z, Howard A, Kelley C, Delogu G, Collins F, Morris S: Immunogenicity of DNA vaccines expressing tuberculosis proteins fused to tissue plasminogen activator signal sequences. Infect Immun 67:4780-4786, 1999
18. Huygen K: On the use of DNA vaccines for the prophylaxis of mycobacterial diseases. Infect Immun 71:1613-1621, 2003
19. Nor NM, Musa M: Approaches towards the development of a vaccine against tuberculosis: recombinant BCG and DNA vaccine. Tuberculosis (Edinb) 84:102-109, 2004
20. Orme IM, McMurray DN, Belisle JT: Tuberculosis vaccine development: recent progress. Trends Microbiol 9:115-118, 2001
21. Dannenberg AM Jr, Collins FM: Progressive pulmonary tuberculosis is not due to increasing numbers of viable bacilli in rabbits, mice and guinea pigs, but is due to a continuous host response to mycobacterial products. Tuberculosis (Edinb);81(3):229-42, 2001
22. Baldwin SL, D.Souza C, Roberts AD, Kelly BP, Frank AA, Lui MA, Ulmer JB, Huygen K, McMurray DM, Orme IM:
Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Infect Immun 66:2951-2959, 1998
23. Scanga CA, Mohan VP, Yu K, Joseph H, Tanaka K, Chan J, Flynn JL: Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2. J Exp Med 192:347-358, 2000
24. Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ: The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med 193:271-280, 2001
25. McMurray DN: Recent progress in the development and testing of vaccines against human tuberculosis. Int J Parasitol 33:547-554, 2003
26. McMurray DN: A nonhuman primate model for preclinical testing of new tuberculosis vaccines. Clin Infect Dis 30 Suppl 3:S210-212, 2000
27. Good RC: Diseases in Nonhuman Primates. In The Mycobacteria. A Sourcebook. Kubica G, Wayne L (eds). New York, Marcel Dekker. Inc., 1984, pp 903-924
28. VandeBerg JL, Williams-Blangero S: Advantages and limitations of nonhuman primates as animal models in genetic research on complex diseases. J Med Primatol 26:113-119, 1997
29. Walsh GP, Tan EV, dela Cruz EC, Abalos RM, Villahermosa LG, Young LJ, Cellona RV, Nazareno JB, Horwitz MA: The Philippine cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model of tuberculosis that resembles human disease. Nat Med 2:430-436, 1996
30. Capuano SV, III, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, Bissel S, Fuhrman C, Klein E, Flynn JL: Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun 71:5831-5844, 2003
31. Langermans JA, Andersen P, van Soolingen D, Vervenne RA, Frost PA, van der Laan T, van Pinxteren LA, van den Hombergh J, Kroon S, Peekel I, Florquin S, Thomas AW: Divergent effect of bacillus Calmette-Guerin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc Natl Acad Sci U S A 98:11497-11502, 2001
32. Baer JF: Husbandry and medical management of the owl monkey. In Aotus: The owl monkey Baer JF, Weller RE, Kakoma I (eds). New York, Academic Press Inc., 1994, pp 133-164
33. Attanasio R, Pehler K, McClure HM: Immunogenicity and safety of Mycobacterium tuberculosis culture filtrate proteins in nonhuman primates. Clin Exp Immunol 119:84-91, 2000
34. Pehler K, Brasky KM, Butler TM, Attanasio R: Mycobacterium tuberculosis-secreted protein antigens: immunogenicity in baboons. J Clin Immunol 20:306-316, 2000
35. Berthet FX, Rasmussen PB, Rosenkrands I, Andersen P, Gicquel B: A Mycobacterium tuberculosis operon encoding ESAT-6 and a novel low-molecular-mass culture filtrate protein (CFP-10). Microbiology 144 ( Pt 11):3195-3203, 1998
36. Gey Van Pittius NC, Gamieldien J, Hide W, Brown GD, Siezen RJ, Beyers AD: The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria. Genome Biol 2:RESEARCH0044, 2001
37. Sorensen AL, Nagai S, Houen G, Andersen P, Andersen AB: Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect Immun 63:1710-1717, 1995
38. Harboe M, Oettinger T, Wiker HG, Rosenkrands I, Andersen P: Evidence for occurrence of the ESAT-6 protein in Mycobacterium tuberculosis and virulent Mycobacterium bovis and for its absence in Mycobacterium bovis BCG. Infect Immun 64:16-22, 1996
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DOI: http://dx.doi.org/10.22490/24629448.344
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