RESUMEN

Los virus: 1) sincitial respiratorio, 2) sarampión, 3) parainfluenza y 4) parotiditis, son los virus de la familia Paramixoviridae con mayor incidencia en el hombre. Estos virus son inductores eficientes de la producción de interferón de tipo I y II (IFN-α/β y γ), y en los últimos años ha quedado claro que éstos comparten proteínas que actúan en la regulación del sistema inmune. La mayoría de los paramixovirus codifican para proteínas que activan mecanismos inhibidores de la producción de los IFNs, disminuyendo la eficiencia de la respuesta inmunológica. En este artículo se mencionan eventos que llevan a la producción de los IFNs mediada por los receptores de reconocimiento de patrones (PRR’s) que a su vez son activados por patrones moleculares asociados a patógenos o PAMPs de cada uno de estos virus. Se describe cómo interaccionan las diferentes proteínas virales (P/V/C, G y NS1 y 2) con su célula blanco y se describe cómo estos cuatro paramixovirus limitan la producción de PAMPs e inhiben las respuestas celulares al interferir con las actividades de los PRR’s, MDA5 y RIG-I, inhibiendo así a diversos componentes de la vía de señalización en la inducción de los IFNs.

PALABRAS CLAVE

Interferón, Paramyxoviridae, PAMPs, PRR’s, TLR’s, MDA5, RIG-I.

REFERENCIAS

1. Knipe DM, Howley PM, Griffin DE, et al. Fields virology. Vol 1. 5a ed. USA: Lippincott Williams & Wilkins; 2007: p. 3177.

2. Chambers R, Takimoto T. Antagonism of innate immunity by paramyxovirus accessory proteins. Viruses 2009;1:574-593.

3. Goodbourn S, Randall RE. The regulation of type I interferon production by paramyxoviruses. J Interferon Cytokine Res 2009;29:539-547.

4. Magnusson L. Analysis of the human parainfluenza virus replication promoter. UW-L J Und Res X 2007:1-4.

5. Cabello RR. Microbiología y parasitología humana: bases etiológicas de las enfermedades infecciosas. 2a. ed. México: Médica Panamericana; 2007:p. 873.

6. Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol 2009;83:1492-1500.

7. Martinez-Sobrido L, Gitiban N, Fernández-Sesma A, et al. Protection against respiratory syncytial virus by a recombinant Newcastle disease virus vector. J Virol 2006;83:1130-1139.

8. Flynn M, Mahon BP. Cell mediated and humoral immune responses to mumps virus. Recent Research in Virology; 2003:97-115.

9. Enders G. Paramyxoviruses: mumps virus. In: Barron S, Albrecht T, Castro G, et al. Barron’s medical microbiology. USA: Univ of Texas Medical Branch; 1996.p.1132-1155.

10. Furuse Y, Suzuki A, Oshitani H. Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries. J Virol 2010;7:1-4.

11. Yanagi Y, Takeda M, Ohno S. Measles virus: cellular receptors, tropism and pathogenesis. J Gen Virol 2006;87:2767-2779.

12. Kohlmeier JE, Woodland DL. Immunity to respiratory viruses. Annu Rev Immunol 2009;27:61-82.

13. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 4th. ed. New York: Churchill Livingstone; 2006:p.35.

14. Asselin-Paturel C, Boonstra A, Dalod M, et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2001;2:1144-1150.

15. Kondo K, Bando H, Tsurudome M, Kawano M, Nishio M, Ito Y. Sequence analysis of the phosphoprotein (P) genes of human parainfluenza type 4A and 4B viruses and RNA editing at transcript of the P genes: the number of G residues added is imprecise. Virology 1990;178:321-326.

16. Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology. Viruses: structure, function. 4th. ed. New York, NY: Freeman; 2001:p.1084.

17. Latorre P, Kolakofsky D, Curran J. Sendai virus Y proteins are initiated by a ribosomal shunt. Mol Cell Biol 1998;18:5021-5031.

18. Rixon H, Brown G, Aitken J, McDonald T, Graham S, Sugrue R J. The small hydrophobic (SH) protein accumulates within lipid-raft structures of the Golgi complex during respiratory syncytial virus infection. J Gen Virol 2004;85:1153-1165.

19. Jack PJ, Boyle DB, Eaton BT, Wang LF. The complete genome sequence of J virus reveals a unique genome structure in the family paramyxoviridae. J Virol 2005;79:10690-10700.

20. Bourgeois C, Bour JB, Lidholt K, Gauthray C, Pothier P. Heparin-like structures on respiratory syncytial virus are involved in its infectivity in vitro. J Virol 1998;72:7221-7227.

21. Satake M, Coligan JE, Elango N, Norrby E, Venkatesan S. Respiratory syncytial virus envelope glycoprotein (G) has a novel structure. Nucleic Acids Res 1985;13:7795-7812.

22. Lamb RA, Jardetzky TS. Structural basis of viral invasion: lessons from paramyxovirus F. Curr Opin Struct Biol 2007;17:427-436.

23. Vergara HSJ, Gutiérrez MA, Mohapatra SS. Biología molecular del virus sincitial respiratorio y desarrollo de estrategias profilácticas. Salud Uninorte Barranquilla (Col.) 2006;22:135-153.

24. Melchjorsen J, Jensen SB, Malmgaard L, et al. Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell type-specific manner. J Virol 2005;79:12944-12951.

25. Herold S, von Wulffen W, Steinmueller M, et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: Impact of chemokines and adhesion molecules. J Immunol 2006;177:1817-1824.

26. Wareing MD, Lyon A, Inglis C, Giannoni F, Charo I, Sarawar SR. Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2−/−mice. J Leukoc Biol 2007;81:793-801.

27. Chan MC, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by Influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 2005;6:135.

28. Uematsu S, Akira S. Toll-like receptors and Type I interferons. J Biol Chem 2007;282:15319-15323.

29. Pestka S. The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 2007;282:20047-20051.

30. González-Navajas J, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol 2012;12:125-135.

31. Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res 2006;26:373-379.

32. Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 2003;4:63-68.

33. Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008; 89:1-47.

34. Goodbourn, S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 2000; 81:2341-2364.

35. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998;67:227-264.

36. Fontana JM, Bankamp B, Rota PA. Inhibition of interferon induction and signaling by paramyxoviruses. Immunol Rev 2008;225:46-67.

37. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol 1997;15:749-795.

38. Weber F, Kochs G, Haller O. Inverse interference: how viruses fight the interferon system. Viral Immunol 2004;17:498-515.

39. Frahm T, Hauser H, Köster M. IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export. J Cell Sci 2006;119:1092-1104.

40. Haller O, Kochs G, Weber F. The interferon response circuit: induction and suppression by pathogenic viruses. Virology 2006;344:119-130.

41. Segovia J, Sabbah A, Mgbemena V, et al. TLR2/MyD88/NF-kB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS One 2012;7: e29695.

42. Garofalo RP, Haeberle H. Epithelial regulation of innate immunity to respiratory syncytial virus. Am J Respir Cell Mol Biol 2000;23:581-585.

43. McNamara PS, Smyth RL. The pathogenesis of respiratory syncytial virus disease in childhood. Br Med Bull 2002;61:13-28.

44. Wang SZ, Forsyth KD. The interaction of neutrophils with respiratory epithelial cells in viral infection. Respirology 2000;5:1-10.

45. Kimpen JL. Respiratory syncytial virus and asthma. The role of monocytes. Am J Respir Crit Care Med 2001;163(3 Pt 2):S7-S9.

46. Domachowske JB, Rosenberg HF. Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment. Clin Microbiol Rev 1999;12:298-309.

47. Klein KP, Tan L W, van Bleek GM, Coenjaerts F. The role of Toll-like receptors in regulating the immune response against respiratory syncytial virus. Crit Rev Immunol 2009;29:531-550.

48. Kawai T, Akira S. TLR signaling. Semin Immunol 2007:19:24-32.

49. Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006;441:101-105.

50. Bhoj VG, Sun Q, Bhoj EJ, et al. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. Proc Natl Acad Sci USA 2008;105:14046-14051.

51. Takeuchi O, Akir S. Innate immunity to virus infection. Immunol Rev 2009;227:75-86.

52. Braciale TJ, Sun J, Kim TS. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol 2012;12:295-305.

53. Karin M, Ben-Neriah MY. Phosphorylation meets ubiquitination: the control of NF-[kappa] B activity. Annu Rev Immunol 2000;18:621-663.

54. Kruijsen D. Mechanisms of respiratory syncytial virus specific T cell activation. Igitur.archive.library.com. 2011. Access date: September 21, 2012. Available from: http://igitur-archive.library.uu.nl/dissertations/2011-1024-200516/kruijsen.pdf

55. Shingai M, Azuma M, Ebihara T, et al. Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction. Int Immunol 2008;20:1169-1180.

56. Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages. J Virol 2004;78:4363-4369.

57. Elliott J, Lynch OT, Suessmuth Y, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J Virol 2007;81:3428-3436.

58. Jewell NA, Vaghefi N, Mertz SE, et al. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J Virol 2007;81:9790-9800.

59. Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappa B, and proinflammatory cytokines. J Virol 2005;79:5353-5362.

60. Valarcher JF, Furze J, Wyld S, Cook R, Conzelmann KK, Taylor GJ. Role of alpha/beta interferons in the attenuation and immunogenicity of recombinant bovine respiratory syncytial viruses lacking NS proteins. J Virol 2003;77:8426-8439.

61. Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 2000;1:398-401.

62. Wilson RL, Fuentes SM, Wang P, et al. Function of small hydrophobic proteins of paramyxovirus. J Virol 2006;80:1700-1709.

63. Fuentes S, Tran KC, Luthra P, Teng MN, He B. Function of the respiratory syncytial virus small hydrophobic protein. J Virol 2007;81:8361-8366.

64. Krilov LR, Hendry RM, Godfrey E, McIntosh K. Respiratory virus infection of peripheral blood monocytes: correlation with ageing of cells and interferon production in vitro. J Gen Virol 1987;68:1749-1753.

65. Bose S, Kar N, Maitra R, DiDonato JA, Banerjee AK. Temporal activation of NF-kappaB regulates an interferon-independent innate antiviral response against cytoplasmic RNA viruses. Proc Natl Acad Sci USA 2003;100:10890-10895.

66. Sabbah A, Bose S. Retinoic acid inducible gene I activates innate antiviral response against human parainfluenza virus type 3. J Virol 2009;6:200.

67. Gao J, De BP, Han Y, Choudhary S, Ransohoff R, Banerjee AK. Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon. J Virol 2001;75:1124-1131.

68. Young DF, Didcock L, Goodbourn S, Randall RE. Paramyxoviridae use distinct virus-specific mechanisms to circumvent the interferon response. Virology 2000;269:383-390.

69. Choudhary S, Gao J, Leaman DW, De BP. Interferon action against human parainfluenza virus type 3: Involvement of a novel antiviral pathway in the inhibition of transcription. J Virol 2001;75:4823-4831.

70. Andrejeva J, Childs KS, Young DF, et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN beta promoter. Proc Natl Acad Sci USA 2004;101:17264-17269.

71. Schaap-Nutt A, D’Angelo C, Scull MA, et al. Human parainfluenza virus type 2 V protein inhibits interferon production and signaling and is required for replication in non human primates. Virology 2010;397:285-298.

72. Okada H, Sato TA, Katayama A, et al. Comparative analysis of host responses related to immunosuppression between measles patients and vaccine recipients with live attenuated measles vaccines. Arch Virol 2001;146:859-874.

73. Vilcek J, Sen GC. Interferons and other cytokines. In: Fields BN, Knipe DM, Howley PM, et al. Fundamental virology. 3rd ed. New York, NY: Lippincott-Raven Press; 1996:p.341-365.

74. Ryon JJ, Moss WJ, Monze M, Griffin DE. Functional and phenotypic changes in circulating lymphocytes from hospitalized zambian children with measles. Clin Diagn Lab Immunol 2002;9:994-1003.

75. Hengel H, Koszinowski UH, Conzelmann KK. Viruses know it all: new insights into IFN networks. Trends Immunol 2005;26:396-401.

76. García-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in détente. Science 2006;312:879-882.

77. Ohno S, Ono N, Takeda M, Takeuchi K, Yanagi Y. Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction. J Gen Virol 2004;85:2991-2999.

78. Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005;434:772-777.

79. Nakatsu Y, Takeda M, Ohno S, Shirogane Y, Iwasaki M, Yanagi Y. Measles virus circumvents the host interferon response by different actions of the C and V proteins. J Virol 2008;82:8296-8306.

80. Takaki H, Watanabe Y, Shingai M, Oshiumi H, Matsumoto M, Seya T. Strain-to-strain difference of V protein of measles virus affects MDA5-mediated IFN-b-inducing potential. Mol Immunol 2011;48:1589-1590

81. Pfaller CK, Conzelmann KK. Measles virus V protein is a decoy substrate for IkappaB kinase alpha and prevents Toll-like receptor 7/9-mediated interferon induction. J Virol 2008;82:12365-12373.

82. Lu LL, Puri M, Horvath CM, Sen GC. Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1. J Biol Chem 2008;283:14269-14276.

83. Ulane CM, Rodriguez JJ, Parisien JP, Horvath CM. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol 2003;77:6385-6393.

84. Yoo KH, Agarwal K, Butterfield M, Jacobson RM, Poland GA, Juhn YJ. Assessment of humoral and cell-mediated immune response to measles-mumps-rubella vaccine viruses among patients with asthma. Allergy Asthma Proc 2010;31:499-506.

85. Kubota T, Yokosawa N, Yokota S, Fujii N, Tashiro M, Kato A. Mumps virus V protein antagonizes interferon without the complete degradation of STAT1. J Virol 2005;79:4451-4459.

86. Yokosawa N, Yokota S, Kubota T, Fujii N. C-terminal region of STAT-1alpha is not necessary for its ubiquitination and degradation caused by mumps virus V protein. J Virol 2002;76:12683-12690.

87. Xu P, Luthra P, Li Z, et al. The V protein of mumps virus plays a critical role in pathogenesis. J Virol 2012;86:1768-1776.