Virologica Sinica

, Volume 30, Issue 3, pp 190–199 | Cite as

A respiratory syncytial virus persistent-infected cell line system reveals the involvement of SOCS1 in the innate antiviral response

  • Junwen Zheng
  • Pu Yang
  • Yan Tang
  • Dongchi ZhaoEmail author
Research Article


HEp-2 cells persistently infected with respiratory syncytial virus (RSV) are a heterogeneous mixture of viral antigen-positive and -negative variants; however, the mechanism through which viral replication becomes latent remains unclear. In this study, we investigated the potential mechanism by which RSV escapes from innate immune surveillance. Persistent-infected RSV HEp-2 cells were isolated and cell clones were passaged. The RSV-persistent cells produced viruses at a lower titer, resisted wild-type RSV re-infection, and secreted high levels of interferon-ß (IFN-ß), macrophage inflammatory protein-1α (Mip-1α), interleukin-8 (IL-8), and Rantes. Toll-like receptor 3 (TLR3), retinoic acid inducible gene-I (RIG-I), and suppressor of cytokine signaling 1 (SOCS1) levels were upregulated in these cells. The silencing of TLR3 mRNA decreased the expression of SOCS1 protein and the secretion of cytokines. RSV-persistent cells are in an inflammatory state; upregulation of SOCS1 is related to the TLR3 signaling pathway, which could be associated with the mechanism of viral persistence.


respiratory syncytial virus (RSV) suppressor of cytokine signaling 1 (SOCS1) interferon toll-like receptor 3 (TLR3) RSV-persistent cell line 


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  1. Baetz A, Frey M, Heeg K, Dalpke AH. 2004. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. J Biol Chem, 279: 54708–54715.PubMedCrossRefGoogle Scholar
  2. Bangham CRM, McMichael AJ. 1986. Specific human cytotoxic T cells recognize B cell lines persistently infected with respiratory syncytial virus. Proc Natl Acad Sci USA, 83: 9183–9187.PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Häussinger D. 2003. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb J, 17: 488–490.PubMedGoogle Scholar
  4. Borg I, Rohde G, Löseke S, Bittscheidt J, Schultze-Werninghaus G, Stephan V, Bufe A. 2003. Evaluation of quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases. Eur Respir J, 21: 944–951.PubMedCrossRefGoogle Scholar
  5. Dalpke A, Heeg K, Bartz H, Baetz A. 2008. Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins. Immunobiology, 213: 225–235.PubMedCrossRefGoogle Scholar
  6. Falsey AR, Formica MA, Hennessey PA, Criddle MM, Sullender WM, Walsh EE. 2006. Detection of respiratory syncytial virus in adults with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 173:639–643.PubMedCentralPubMedCrossRefGoogle Scholar
  7. Groskreutz DJ, Monick MM, Powers LS, Yarovinsky TO, Look DC, Hunninghake GW. 2006. Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol, 176: 1733–1740.PubMedCrossRefGoogle Scholar
  8. Hashimoto K, Ishibashi K, Ishioka K, Zhao D, Sato M, Ohara S, Abe Y, Kawasaki Y, Sato Y, Yokota S, Fujii N, Peebles RS Jr, Hosoya M, Suzutani T. 2009. RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules. Virology, 391:162–170.PubMedCrossRefGoogle Scholar
  9. Herranz C, Melero JA, Martínez I. 2011. Reduced innate immune response, apoptosis, and virus release in cells cured of respiratory syncytial virus persistent infection. Virology, 410: 56–63.PubMedCrossRefGoogle Scholar
  10. Hobson L, Everard ML. 2008. Persistent of respiratory syncytial virus in human dendritic cells and influence of nitric oxide. Clin Exp Immun, 151: 359–366.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Jeanette I, Webster M, Jacqueline C. 2013. Poly I:C and respiratory syncytial virus (RSV) inhibit glucocorticoid receptor (GR)-mediated transactivation in lung epithelial, but not monocytic, cell lines. Virus Res,176: 303–306.CrossRefGoogle Scholar
  12. Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, Si-Tahar M. 2007. Cutting Edge: Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol, 178: 3368–3372.PubMedCrossRefGoogle Scholar
  13. Liu P, Jamaluddin M, Li K, Garofalo RP, Casola A, Brasier AR. 2007. Retinoic acid inducible gene-I mediates early anti-viral response and toll like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. J Virol, 81: 1401–1411.PubMedCentralPubMedCrossRefGoogle Scholar
  14. Martínez I, Lombardía L, Herranz C, García-Barreno B, Domínguez O, Melero JA. 2009. Cultures of HEp-2 cells persistently infected by human respiratory syncytial virus differ in chemokine expression and resistance to apoptosis as compared to lytic infections of the same cell type. Virology, 388: 31–41.PubMedCrossRefGoogle Scholar
  15. Matsuse H, Behera AK, Kumar M, Rabb H, Lockey RF, Mohapatra SS. 2000. Recurrent respiratory syncytial virus infections in allergen-sensitized mice lead to persistent airway inflammation and hyperresponsiveness. J Immunol, 164: 6583–6592.PubMedCrossRefGoogle Scholar
  16. Oshansky CM, Krunkosky TM, Barber J, Jones LP, Tripp RA. 2009. Respiratory syncytial virus proteins modulate suppressors of cytokine signaling 1 and 3 and the type I interferon response to infection by a toll-like receptor pathway. Viral Immunol, 22: 147–161.PubMedCrossRefGoogle Scholar
  17. Pothlichet J, Chignard M, Si-Tahar M. 2008. Cutting Edge: Innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway. J Immunol, 80: 2034–2038.CrossRefGoogle Scholar
  18. Prêle CM, Woodward EA, Bisley J, Keith-Magee A, Nicholson SE, Hart PH. 2008. SOCS1 regulates the IFN but not NFκB pathway in TLR-stimulated human monocytes and macrophages. J Immunol, 181: 8018–8026.PubMedCentralPubMedCrossRefGoogle Scholar
  19. Psarras S, Papadopoulos NG, Johnston SL. 2004. Pathogenesis of respiratory syncytial virus bronchiolitis-related wheezing. Paediatr Respir Rev, (Suppl A): 179–184.Google Scholar
  20. Riedel F, Oberdieck B, Streckert HJ, Philippou S, Krusat T, Marek W. 1997. Persistence of airway hyperresponsiveness and viral antigen following respiratory syncytial virus bronchiolitis in young guinea-pigs. Eur Respir J, 10: 639–645.PubMedGoogle Scholar
  21. Schwarze J, O’Donnell DR, Rohwedder A, Openshaw PJ. 2004. Latency and persistence of respiratory syncytial virus despite T cell immunity. Am J Respir Crit Care Med, 169: 801–805.PubMedCrossRefGoogle Scholar
  22. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, Wedzicha JA. 2001. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 164: 1618–1623.PubMedCrossRefGoogle Scholar
  23. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. 2000. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit. Care Med, 161: 1501–1507.Google Scholar
  24. Sikkel MB, Quint JK, Mallia P, Wedzicha JA, Johnston SL. 2008. Respiratory syncytial virus persistence in chronic obstructive pulmonary disease. Pediatr Infect Dis J, 27(Suppl): 63–70.CrossRefGoogle Scholar
  25. Stowell NC, Seideman J, Raymond HA, Smalley KA, Lamb RJ, Egenolf DD, Bugelski PJ, Murray LA, Marsters PA, Bunting RA, Flavell RA, Alexopoulou L, San Mateo LR, Griswold DE, Sarisky RT, Mbow ML, Das AM. 2009. Long-term activation of TLR3 by Poly (I: C) induces inflammation and impairs lung function in mice. Respir Res, 10: 43.PubMedCentralPubMedCrossRefGoogle Scholar
  26. Tripp RA. 2004. The brume surrounding respiratory syncytial virus persistence. Am. J Respir Crit Care Med, 169: 778–779.PubMedCrossRefGoogle Scholar
  27. Valdovinos MR, Gomez B. 2003. Establishment of respiratory syncytial virus persistence in cell lines: association with defective interfering particles. Intervirology, 46:190–198.PubMedCrossRefGoogle Scholar
  28. Vlotides G, Sörensen AS, Kopp F, Zitzmann K, Cengic N, Brand S, Zachoval R, Auernhammer CJ. 2004. SOCS-1 and SOCS-3 inhibit IFN-alpha-induced expression of the antiviral proteins 2,5-OAS and MxA. Biochem Biophys Res Commun, 320: 1007–1014.PubMedCrossRefGoogle Scholar
  29. Xu X, Zheng J, Zheng K, Hou Y, Zhao F, Zhao D. 2014. Respiratory syncytial virus NS1 protein degrades STAT2 by inducing SOCS1 expression. Intervirology, 57: 65–73.PubMedGoogle Scholar
  30. Yasukawa H, Yajima T, Duplain H, Iwatate M, Kido M, Hoshijima M, Weitzman MD, Nakamura T, Woodard S, Xiong D, Yoshimura A, Chien KR, Knowlton KU. 2003. The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. J Clin Invest, 111: 469–478.PubMedCentralPubMedCrossRefGoogle Scholar
  31. Zhao DC, Tang Y, Li L, You SY, Zhang CY. 2007. Respiratory syncytial virus inhibits interferon-a-inducible signaling in macrophage- like U937 cells. J Infect, 54: 393–398.PubMedCrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of PediatricsZhongnan Hospital of Wuhan UniversityWuhanChina
  2. 2.Department of Anatomy, School of MedicineWuhan UniversityWuhanChina

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