Papel del TGF-β en la inmunidad contra los rotavirus


La vía de entrada y el principal sitio de replicación de los rotavirus es el intestino delgado. En este órgano el TGF-β juega un papel muy importante para mantener la tolerancia a los alimentos y microorganismos comensales. Por esta razon, es probable que esta citocina juegue un papel modulador en esta infección. Experimentos in vitro de nuestro laboratorio han mostrado que células humanas epiteliales infectadas por rotavirus aumentan la secreción de TGF-β y promueven una baja respuesta de linfocitos T, la que es necesaria para la inmunidad antiviral. En este artículo de revisión se analiza en forma crítica la hipótesis que los rotavirus inducen la producción de TGF-β como mecanismo de evasión inmune. © 2016. Acad. Colomb. Cienc. Ex. Fis. Nat. Todos los derechos reservados.


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Aghajani, K., Keerthivasan, S., Yu, Y., Gounari, F. 2012. Generation of CD4CreER(T(2)) transgenic mice to study development of peripheral CD4-T-cells. Genesis50 (12): 908-913.

Allen, S.J., Mott, K.R., Wechsler, S.L., Flavell, R.A., Town, T., Ghiasi, H. 2011. Adaptive and innate transforming growth factor beta signaling impact herpes simplex virus 1 latency and reactivation. J Virol85 (21): 11448-11456.

Angel, J., Franco, M.A., Greenberg, H.B. 2012. Rotavirus immune responses and correlates of protection. Curr Opin Virol 2 (4): 419-425.

Angel, J., Steele, A.D., Franco, M.A. 2014. Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges. Hum Vaccin Immunother 10 (12): 3659-3671.

Arnold, M.M., Patton, J.T. 2011. Diversity of interferon antagonist activities mediated by NSP1 proteins of different rotavirus strains. J Virol 85 (5): 1970-1979.

Azevedo, M.S., Yuan, L., Pouly, S., Gonzales, A.M., Jeong, K.I., Nguyen, T.V., Saif, L.J. 2006. Cytokine responses in gnotobiotic pigs after infection with virulent or attenuated human rotavirus. J Virol80 (1): 372-382.

Azevedo, M.S., Zhang, W., Wen, K., Gonzalez, A.M., Saif, L.J., Yousef, A.E., Yuan, L. 2012. Lactobacillus acidophilus and Lactobacillus reuteri modulate cytokine responses in gnotobiotic pigs infected with human rotavirus. Benef Microbes3 (1): 33-42.

Barreto, A., Rodriguez, L.-S., Lucia Rojas, O., Wolf, M., Greenberg, H.B., Franco, M.A., Angel, J. 2010. Membrane Vesicles Released by Intestinal Epithelial Cells Infected with Rotavirus Inhibit T-Cell Function. Viral Immunology 23 (6): 595-608.

Barro, M., Patton, J.T. 2005. Rotavirus nonstructural protein 1 subverts innate immune response by inducing degradation of IFN regulatory factor 3. Proc Natl Acad Sci U S A102(11): 4114-4119.

Boettler, T., Cheng, Y., Ehrhardt, K., von Herrath, M. 2012. TGF-beta blockade does not improve control of an established persistent viral infection. Viral Immunol 25 (3): 232-238.

Broquet, A.H., Hirata, Y., McAllister, C.S., Kagnoff, M.F. 2011. RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium. J Immunol186 (3): 1618-1626.

Chattha, K.S., Vlasova, A.N., Kandasamy, S., Rajashekara, G., Saif, L.J. 2013. Divergent immunomodulating effects of probiotics on T cell responses to oral attenuated human rotavirus vaccine and virulent human rotavirus infection in a neonatal gnotobiotic piglet disease model. J Immunol 191 (5): 2446-2456.da

Cunha, A.P., Wu, H.Y., Rezende, R.M., Vandeventer, T., Weiner, H.L. 2015. In vivo anti-LAP mAb enhances IL-17/IFN-gamma responses and abrogates anti-CD3-induced oral tolerance. Int Immunol 27 (2): 73-82.

Feng, N., Sen, A., Nguyen, H., Vo, P., Hoshino, Y., Deal, E.M., Greenberg, H.B. 2009. Variation in antagonism of the interferon response to rotavirus NSP1 results in differential infectivity in mouse embryonic fibroblasts. J Virol 83 (14): 6987-6994.

Franco, M.A., Angel, J., Greenberg, H.B. 2006. Immunity and correlates of protection for rotavirus vaccines. Vaccine 24(15): 2718-2731.

Franco, M.A., Greenberg, H.B. 1995. Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J Virol 69 (12): 7800-7806.

Franco, M.A., Greenberg, H.B. 1997. Immunity to rotavirus in T cell deficient mice. Virology 238 (2): 169-179.

Freeman, B.E., Meyer, C., Slifka, M.K. 2014. Anti-inflammatory cytokines directly inhibit innate but not adaptive CD8+ T cell functions. J Virol88 (13): 7474-7484.

Gagliani, N., Vesely, M.C., Iseppon, A., Brockmann, L., Xu, H., Palm, N.W., de Zoete, M.R., Licona-Limon, P., Paiva, R.S., Ching, T., Weaver, C., Zi, X., Pan, X., Fan, R., Garmire, L.X., Cotton, M.J., Drier, Y., Bernstein, B., Geginat, J., Stockinger, B., Esplugues, E., Huber, S., Flavell, R.A. 2015. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523 (7559): 221-5

Garidou, L., Heydari, S., Gossa, S., McGavern, D.B. 2012. Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection. J Virol 86 (13): 7060-7071.

Gibbs, J.D., Ornoff, D.M., Igo, H.A., Zeng, J.Y., Imani, F.2009. Cell cycle arrest by transforming growth factor beta1 enhances replication of respiratory syncytial virus in lung epithelial cells. J Virol 83 (23): 12424-12431.

Graff, J.W., Ettayebi, K., Hardy, M.E. 2009. Rotavirus NSP1 inhibits NFkappaB activation by inducing proteasome-dependent degradation of beta-TrCP: a novel mechanism of IFN antagonism. PLoS Pathog5 (1): e1000280.

Ishigame, H., Mosaheb, M.M., Sanjabi, S., Flavell, R.A. 2013a. Truncated form of TGF-betaRII, but not its absence, induces memory CD8+ T cell expansion and lymphoproliferative disorder in mice. J Immunol 190 (12): 6340-6350

Ishigame, H., Zenewicz, L.A., Sanjabi, S., Licona-Limon, P., Nakayama, M., Leonard, W.J., Flavell, R.A. 2013b. Excessive Th1 responses due to the absence of TGF-beta signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc Natl Acad Sci U S A110 (17): 6961-6966.

Jaimes, M.C., Feng, N., Greenberg, H.B. 2005. Characterization of homologous and heterologous rotavirus-specific T-cell responses in infant and adult mice. J Virol 79 (8): 4568-4579.

Jung, H.C., Eckmann, L., Yang, S.K., Panja, A., Fierer, J., Morzycka-Wroblewska, E., Kagnoff, M.F. 1995. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest95 (1): 55-65.

Karimi-Googheri, M., Daneshvar, H., Nosratabadi, R., Zare-Bidaki, M., Hassanshahi, G., Ebrahim, M., Arababadi, M.K., Kennedy, D. 2014. Important roles played by TGF-beta in hepatitis B infection. J Med Virol 86 (1): 102-108.

Kim, B., Feng, N., Narvaez, C.F., He, X.S., Eo, S.K., Lim, C.W., Greenberg, H.B. 2008. The influence of CD4+ CD25+ Foxp3+ regulatory T cells on the immune response to rotavirus infection. Vaccine 26 (44): 5601-5611.

Kim, D., Lee, A.S., Jung, Y.J., Yang, K.H., Lee, S., Park, S.K., Kim, W., Kang, K.P. 2014. Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor alpha-mediated transforming growth factor-beta1/Smad signaling pathway. Nephrol Dial Transplant 29 (11): 2043-2053.

Kindrachuk, J., Wahl-Jensen, V., Safronetz, D., Trost, B., Hoenen, T., Arsenault, R., Feldmann, F., Traynor, D., Postnikova, E., Kusalik, A., Napper, S., Blaney, J.E., Feldmann, H., Jahrling, P.B. 2014. Ebola virus modulates transforming growth factor beta signaling and cellular markers of mesenchyme-like transition in hepatocytes. J Virol 88 (17): 9877-9892.

Kocher, J., Bui, T., Giri-Rachman, E., Wen, K., Li, G., Yang, X., Liu, F., Tan, M., Xia, M., Zhong, W., Jiang, X., Yuan, L.2014. Intranasal P particle vaccine provided partial cross-variant protection against human GII.4 norovirus diarrhea in gnotobiotic pigs. J Virol 88 (17): 9728-9743.

Lanteri, M.C., O’Brien, K.M., Purtha, W.E., Cameron, M.J., Lund, J.M., Owen, R.E., Heitman, J.W., Custer, B., Hirschkorn, D.F., Tobler, L.H., Kiely, N., Prince, H.E., Ndhlovu, L.C., Nixon, D.F., Kamel, H.T., Kelvin, D.J., Busch, M.P., Rudensky, A.Y., Diamond, M.S., Norris, P.J. 2009. Tregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest 119 (11): 3266-3277.

Lewis, G.M., Macal, M., Hesser, C., Zuniga, E.I. 2015. Consti-tutive But Not Inducible Attenuation Of Transforming Growth Factor-beta Signaling Increases Natural Killer Cell Responses Without Directly Affecting Dendritic Cells Early After Chronic Viral Infection. J Virol.

Li, N., Ren, A., Wang, X., Fan, X., Zhao, Y., Gao, G.F., Cleary, P., Wang, B. 2015. Influenza viral neuraminidase primes bacterial coinfection through TGF-beta-mediated expression of host cell receptors. Proc Natl Acad Sci U S A 112 (1): 238-243

Lin, A.H., Luo, J., Mondshein, L.H., ten Dijke, P., Vivien, D., Contag, C.H., Wyss-Coray, T. 2005. Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury. J Immunol175 (1): 547-554.

Lund, J.M., Hsing, L., Pham, T.T., Rudensky, A.Y. 2008. Coordination of early protective immunity to viral infection by regulatory T cells. Science 320 (5880): 1220-1224.

Maillot, C., Gargala, G., Delaunay, A., Ducrotte, P., Brasseur, P., Ballet, J.J., Favennec, L. 2000. Cryptosporidium parvum infection stimulates the secretion of TGF-beta, IL-8 and RANTES by Caco-2 cell line. Parasitol Res 86(12): 947-949.

Makela, M., Marttila, J., Simell, O., Ilonen, J. 2004. Rotavirus-specific T-cell responses in young prospectively followed-up children. Clin Exp Immunol 137 (1): 173-178.

Makela, M., Oling, V., Marttila, J., Waris, M., Knip, M., Simell, O., Ilonen, J. 2006. Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes. Clin Exp Immunol145 (2): 261-270.

Marcoe, J.P., Lim, J.R., Schaubert, K.L., Fodil-Cornu, N., Matka, M., McCubbrey, A.L., Farr, A.R., Vidal, S.M., Laouar, Y. 2012. TGF-beta is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol 13 (9): 843-850.

Marshall, H.D., Ray, J.P., Laidlaw, B.J., Zhang, N., Gawande, D., Staron, M.M., Craft, J., Kaech, S.M. 2015. The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Elife 4e04851.

Masopust, D., Vezys, V., Usherwood, E.J., Cauley, L.S., Olson, S., Marzo, A.L., Ward, R.L., Woodland, D.L., Lefrancois, L.2004. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol 172 (8): 4875-4882.

McNeal, M.M., Rae, M.N., Ward, R.L. 1997. Evidence that resolution of rotavirus infection in mice is due to both CD4 and CD8 cell-dependent activities. J Virol 71 (11): 8735-8742.

Mesa, M.C., Gutiérrez, L., Duarte-Rey, C., Angel, J., Franco, M.A. 2010. A TGF-β mediated regulatory mechanism modulates the T cell immune response to rotavirus in adults but not in children. Virology 399 (1): 77-86.

Mileti, E., Matteoli, G., Iliev, I.D., Rescigno, M. 2009. Comparison of the immunomodulatory properties of three probiotic strains of Lactobacilli using complex culture systems: prediction for in vivo efficacy. PLoS One 4 (9): e7056.

Miller, A.D., Blutt, S.E., Conner, M.E. 2014. FoxP3+ regulatory T cells are not important for rotavirus clearance or the early antibody response to rotavirus. Microbes Infect 16(1): 67-72

Niess, J.H., Reinecker, H.C. 2006. Dendritic cells: the commanders-in-chief of mucosal immune defenses. Curr Opin Gastroenterol 22 (4): 354-360.

Oida, T., Weiner, H.L. 2010. TGF-beta induces surface LAP expression on murine CD4 T cells independent of Foxp3 induction. PLoS One5 (11): e15523.

Oida, T., Weiner, H.L. 2011. Murine CD4 T cells produce a new form of TGF-beta as measured by a newly developed TGF-beta bioassay. PLoS One 6 (4): e18365.

Parra, M., Herrera, D., Calvo-Calle, J.M., Stern, L.J., Parra-López, C.A., Butcher, E., Franco, M., Angel, J. 2014a. Circulating human rotavirus specific CD4 T cells identified with a class II tetramer express the intestinal homing receptors α4β7 and CCR9. Virology 452-453: 191-201.

Parra, M., Herrera, D., Jácome, M.F., Mesa, M.C., Rodríguez, L.S., Guzmán, C., Angel, J., Franco, M.A. 2014b. Circulating rotavirus-specific T cells have a poor functional profile. Virology 468-470C:340-350.

Rezende, R.M., Oliveira, R.P., Medeiros, S.R., Gomes-Santos, A.C., Alves, A.C., Loli, F.G., Guimaraes, M.A., Amaral, S.S., da Cunha, A.P., Weiner, H.L., Azevedo, V., Miyoshi, A., Faria, A.M. 2013. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells. J Autoimmun 4045-57.

Rodríguez, L.-S., Barreto, A., Franco, M.A., Angel, J. 2009. Immunomodulators released during rotavirus infection of polarized Caco-2 cells. Viral Immunology 22 (3): 163-172.

Rodriguez, L.S., Narvaez, C.F., Rojas, O.L., Franco, M.A., Angel, J. 2012. Human myeloid dendritic cells treated with supernatants of rotavirus infected Caco-2 cells induce a poor Th1 response. Cell Immunol 272 (2): 154-161.

Sen, A., Pruijssers, A.J., Dermody, T.S., Garcia-Sastre, A., Greenberg, H.B. 2011. The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3. J Virol 85 (8): 3717-3732.

Sledzinska, A., Hemmers, S., Mair, F., Gorka, O., Ruland, J., Fairbairn, L., Nissler, A., Muller, W., Waisman, A., Becher, B., Buch, T. 2013. TGF-beta signalling is required for CD4(+) T cell homeostasis but dispensable for regulatory T cell function. PLoS biology 11 (10): e1001674.

Su, H.C., Ishikawa, R., Biron, C.A. 1993. Transforming growth factor-beta expression and natural killer cell responses during virus infection of normal, nude, and SCID mice. J Immunol151 (9): 4874-4890.

Swiatczak, B., Rescigno, M. 2012. How the interplay between antigen presenting cells and microbiota tunes host immune responses in the gut. Semin Immunol 24 (1): 43-49.

Tinoco, R., Alcalde, V., Yang, Y., Sauer, K., Zuniga, E.I. 2009. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31 (1): 145-157.

Travis, M.A., Sheppard, D. 2014. TGF-beta activation and function in immunity. Annu Rev Immunol 3251-82.

Weiner, H.L., da Cunha, A.P., Quintana, F., Wu, H. 2011. Oral tolerance. Immunol Rev241 (1): 241-259.

Worthington, J.J., Kelly, A., Smedley, C., Bauche, D., Campbell, S., Marie, J.C., Travis, M.A. 2015. Integrin alphavbeta8-Mediated TGF-beta Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation. Immunity 42 (5): 903-915.

Xu, P., Bailey-Bucktrout, S., Xi, Y., Xu, D., Du, D., Zhang, Q., Xiang, W., Liu, J., Melton, A., Sheppard, D., Chapman, H.A., Bluestone, J.A., Derynck, R. 2014. Innate antiviral host defense attenuates TGF-beta function through IRF3-mediated suppression of Smad signaling. Mol Cell 56 (6): 723-737.

Zaccone, P., Burton, O., Miller, N., Jones, F.M., Dunne, D.W., Cooke, A. 2009. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur J Immunol39 (4): 1098-1107.

Zeuthen, L.H., Fink, L.N., Frokiaer, H. 2008. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-beta. Immunology 123 (2): 197-208.

Zhang, N., Bevan, M.J. 2012. TGF-beta signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol 13 (7): 667-673.

Zhang, N., Bevan, M.J. 2013. Transforming growth factor-beta signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39 (4): 687-696.

Cómo citar
Franco-Cortés, M. A. (2016). Papel del TGF-β en la inmunidad contra los rotavirus. Revista De La Academia Colombiana De Ciencias Exactas, Físicas Y Naturales, 40(154), 18-26.
Ciencias biomédicas