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J Med Virol. 2006 Apr; 78(4): 417–424.
Published online 2006 Feb 15. doi: 10.1002/jmv.20556
PMCID: PMC7166776
PMID: 16482545

Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections†

Tamaki Okabayashi, 1 Hiroaki Kariwa, 2 Shin‐ichi Yokota, 1 Shigeo Iki, 1 Tomokazu Indoh, 1 Noriko Yokosawa, 1 Ikuo Takashima, 2 Hiroyuki Tsutsumi, 3 and Nobuhiro Fujiicorresponding author 1
Author information Article notes Copyright and License information PMC Disclaimer

Abstract

The pathogenesis of severe acute respiratory syndrome (SARS) is poorly understood and cytokine dysregulation has been suggested as one relevant mechanism to be explored. We compared the cytokine profile in Caco2 cells after infection of SARS coronavirus (SARS‐CoV) with other respiratory viruses including respiratory syncytial virus (RSV), influenza A virus (FluAV), and human parainfluenza virus type 2 (hPIV2). Interferon (IFN) system (production and response) was not suppressed by SARS‐CoV infection. Therefore, SARS‐CoV replication was suppressed by pretreatment with IFN. SARS‐CoV and RSV induced high levels of IL‐6 and RANTES compared with FluAV and hPIV2. Induction level of suppressor of cytokine signaling‐3 (SOCS3) by SARS‐CoV was significantly lower than that by RSV in spite of the significant production of IL‐6. Toll‐like receptors 4 and 9, which correlate with the induction of inflammatory response, were upregulated by SARS‐CoV infection. Collectively, overinduction of inflammatory cytokine and dysregulation of cytokine signaling may contribute to the immunopathology associated with “severe” inflammation in SARS. J. Med. Virol. 78:417–424, 2006. © 2006 Wiley‐Liss, Inc.

Keywords: SARS‐CoV, SOCS3, cytokine, IL‐6, IFN, TLR

Notes

†This work was performed at Department of Microbiology, Sapporo Medical University School of Medicine, Laboratory of Public Health, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, and Special Pathogens Laboratory, Department of Virology 1, National Institute of Infectious Diseases.

REFERENCES

  • Andrejeva J, Young DF, Goodbourn S, Randall RE. 2002. Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: Consequences for virus replication in the presence of alpha/beta and gamma interferons. J Virol 76: 2159–2167. [PMC free article] [PubMed] [Google Scholar]
  • Chollet‐Martin S, Jourdain B, Gibert C, Elbim C, Chastre J, Gougerot‐Pocidalo MA. 1996. Interaction between neutrophils and chemokines in blood and alveolar spaces during ARDS. Am J Respir Crit Care Med 154: 594–601. [PubMed] [Google Scholar]
  • Cinatl J, Jr. , Michaelis M, Scholz M, Doerr HW. 2004. Role of interferons in the treatment of severe acute respiratory syndrome. Expert Opin Biol Ther 4: 827–836. [PMC free article] [PubMed] [Google Scholar]
  • Fujii N. 1994. 2‐5A and virus infection. Prog Mol Subcell Biol 14: 150–175. [PubMed] [Google Scholar]
  • Fujii T, Nakamura T, Iwamoto A. 2004. Current concepts in SARS treatment. J Infect Chemother 10: 1–7. [PMC free article] [PubMed] [Google Scholar]
  • Gern JE, Martin MS, Anklam KA, Shen K, Roberg KA, Carlson‐Dakes KT, Adler K, Gilbertson‐White S, Hamilton R, Shult PA, Kirk CJ, Da Silva DF, Sund SA, Kosorok MR, Lemanske RF, Jr. 2002. Relationships among specific viral pathogens, virus‐induced interleukin‐8, and respiratory symptoms in infancy. Pediatr Allergy Immunol 13: 386–393. [PubMed] [Google Scholar]
  • Gongora C, David G, Pintard L, Tissot C, Hua TD, Dejean A, Mechti N. 1997. Molecular cloning of a new interferon‐induced PML nuclear body‐associated protein. J Biol Chem 272: 19457–19463. [PubMed] [Google Scholar]
  • Goodbourn S, Didcock L, Randall RE. 2000. Interferons: Cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81: 2341–2364. [PubMed] [Google Scholar]
  • Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S. 2000. A Toll‐like receptor recognizes bacterial DNA. Nature 408: 740–745. [PubMed] [Google Scholar]
  • Heung CY, Poon LLM, Ng IHY, Luk W, Sia S, Wu MHS, Chan K, Yuen K, Gordon S, Guan Y, Peiris JSM. 2005. Cytokine responses in sever acute respiratory syndrome coronavirus‐infected macrophages in vitro: Possible relevance to pathogenesis. J Virol 79: 7819–7826. [PMC free article] [PubMed] [Google Scholar]
  • Holt PG, Sly PD. 2002. Interactions between respiratory tract infections and atopy in the aetiology of asthma. Eur Respir J 19: 538–545. [PubMed] [Google Scholar]
  • Hong TC, Mai QL, Cuong DV, Parida M, Minekawa H, Notomi T, Hasebe F, Morita K. 2004. Development and evaluation of a novel loop‐mediated isothermal amplification method for rapid detection of severe acute respiratory syndrome coronavirus. J Clin Microbiol 42: 1956–1961. [PMC free article] [PubMed] [Google Scholar]
  • Hornsleth A, Klug B, Nir M, Johansen J, Hansen KS, Christensen LS, Larsen LB. 1998. Severity of respiratory syncytial virus disease related to type and genotype of virus and to cytokine values in nasopharyngeal secretions. Pediatr Infect Dis J 17: 1114–1121. [PubMed] [Google Scholar]
  • Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY. 2005. An interferon‐gamma‐related cytokine storm in SARS patients. J Med Virol 75: 185–194. [PMC free article] [PubMed] [Google Scholar]
  • Island ML, Mesplede T, Darracq N, Bandu MT, Christeff N, Djian P, Drouin J, Navarro S. 2002. Repression by homeoprotein pitx1 of virus‐induced interferon a promoters is mediated by physical interaction and trans repression of IRF3 and IRF7. Mol Cell Biol 22: 7120–7133. [PMC free article] [PubMed] [Google Scholar]
  • Kariwa H, Fujii N, Takashima I. 2004. Inactivation of SARS coronavirus by means of povidone‐iodine, physical conditions, and chemical reagents. Jpn J Vet Res 52: 105–112. [PubMed] [Google Scholar]
  • Kubo M, Hanada T, Yoshimura A. 2003. Suppressors of cytokine signaling and immunity. Nat Immunol 4: 1169–1176. [PubMed] [Google Scholar]
  • Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN, Rutschman R, Murray PJ. 2003. SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 4: 546–550. [PubMed] [Google Scholar]
  • Leung WK, To KF, Chan PK, Chan HL, Wu AK, Lee N, Yuen KY, Sung JJ. 2003. Enteric involvement of severe acute respiratory syndrome‐associated coronavirus infection. Gastroenterology 125: 1011–1017. [PMC free article] [PubMed] [Google Scholar]
  • Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. 2003. Angiotensin‐converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450–454. [PMC free article] [PubMed] [Google Scholar]
  • Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA. 2004. Recognition of single‐stranded RNA viruses by Toll‐like receptor 7. Proc Natl Acad Sci USA 101: 5598–5603. [PMC free article] [PubMed] [Google Scholar]
  • Mizutani T, Fukushi S, Murakami M, Hirano T, Saijo M, Kurane I, Morikawa S. 2004a. Tyrosine dephosphorylation of STAT3 in SARS coronavirus‐infected Vero E6 cells. FEBS Lett 577: 187–192. [PMC free article] [PubMed] [Google Scholar]
  • Mizutani T, Fukushi S, Saijo M, Kurane I, Morikawa S. 2004b. Importance of Akt signaling pathway for apoptosis in SARS‐CoV‐infected Vero E6 cells. Virology 327: 169–174. [PMC free article] [PubMed] [Google Scholar]
  • Mizutani T, Fukushi S, Saijo M, Kurane I, Morikawa S. 2004c. Phosphorylation of p38 MAPK and its downstream targets in SARS coronavirus‐infected cells. Biochem Biophys Res Commun 319: 1228–1234. [PMC free article] [PubMed] [Google Scholar]
  • Monick MM, Yarovinsky TO, Powers LS, Butler NS, Carter AB, Gudmundsson G, Hunninghake GW. 2003. Respiratory syncytial virus up‐regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J Biol Chem 278: 53035–53044. [PubMed] [Google Scholar]
  • Morgenstern B, Michaelis M, Baer PC, Doerr HW, Cinatl J, Jr. 2005. Ribavirin and interferon‐beta synergistically inhibit SARS‐associated coronavirus replication in animal and human cell lines. Biochem Biophys Res Commun 326: 905–908. [PMC free article] [PubMed] [Google Scholar]
  • Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS. 2003. Lung pathology of fatal severe acute respiratory syndrome. Lancet 361: 1773–1778. [PMC free article] [PubMed] [Google Scholar]
  • Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY. 2003. Clinical progression and viral load in a community outbreak of coronavirus‐associated SARS pneumonia: A prospective study. Lancet 361: 1767–1772. [PMC free article] [PubMed] [Google Scholar]
  • Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi‐Castagnoli P, Layton B, Beutler B. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282: 2085–2088. [PubMed] [Google Scholar]
  • Poole E, He B, Lamb RA, Randall RE, Goodbourn S. 2002. The V proteins of simian virus 5 and other paramyxoviruses inhibit induction of interferon‐beta. Virology 303: 33–46. [PubMed] [Google Scholar]
  • Ramaswamy M, Shi L, Monick MM, Hunninghake GW, Look DC. 2004. Specific inhibition of type I interferon signal transduction by respiratory syncytial virus. Am J Respir Cell Mol Biol 30: 893–900. [PubMed] [Google Scholar]
  • Sainz B, Jr. , Mossel EC, Peters CJ, Garry RF. 2004. Interferon‐beta and interferon‐gamma synergistically inhibit the replication of severe acute respiratory syndrome‐associated coronavirus (SARS‐CoV). Virology 329: 11–17. [PMC free article] [PubMed] [Google Scholar]
  • Samuel CE. 1991. Antiviral actions of interferon. Interferon‐regulated cellular proteins and their surprisingly selective antiviral activities. Virology 183: 1–11. [PubMed] [Google Scholar]
  • Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T. 2000. Distinct and essential roles of transcription factors IRF‐3 and IRF‐7 in response to viruses for IFN‐alpha/beta gene induction. Immunity 13: 539–548. [PubMed] [Google Scholar]
  • Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki‐Ohara K, Cacalano N, O'Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M. 2003. SOCS‐3 regulates onset and maintenance of T(H)2‐mediated allergic responses. Nat Med 9: 1047–1054. [PubMed] [Google Scholar]
  • Sen GC, Ransohoff RM. 1993. Interferon‐induced antiviral actions and their regulation. Adv Virus Res 42: 57–102. [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • Spiegel M, Pichlmair A, Martinez‐Sobrido L, Cros J, Garcia‐Sastre A, Haller O, Weber F. 2005. Inhibition of beta interferon induction by severe acute respiratory syndrome coronaviruse suggests a two‐step model for activation of interferon regulatory factor 3. J Virol 79: 2079–2086. [PMC free article] [PubMed] [Google Scholar]
  • Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. 1998. How cells respond to interferons. Annu Rev Biochem 67: 227–264. [PubMed] [Google Scholar]
  • Sung RY, Hui SH, Wong CK, Lam CW, Yin J. 2001. A comparison of cytokine responses in respiratory syncytial virus and influenza A infections in infants. Eur J Pediatr 160: 117–122. [PubMed] [Google Scholar]
  • Takeda K, Akira S. 2001. Roles of Toll‐like receptors in innate immune responses. Genes Cells 6: 733–742. [PubMed] [Google Scholar]
  • Talon J, Horvath CM, Polley R, Basler CF, Muster T, Palese P, Garcia‐Sastre A. 2000. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 74: 7989–7996. [PMC free article] [PubMed] [Google Scholar]
  • To KF, Lo AW. 2004. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): The tissue distribution of the coronavirus (SARS‐CoV) and its putative receptor, angiotensin‐converting enzyme 2 (ACE2). J Pathol 203: 740–743. [PMC free article] [PubMed] [Google Scholar]
  • Tsutsumi H, Nagai K, Suga K, Chiba Y, Chiba S, Tsugawa S, Ogra PL. 1989. Antigenic variation of human RSV strains isolated in Japan. J Med Virol 27: 124–130. [PubMed] [Google Scholar]
  • Villard J, Dayer‐Pastore F, Hamacher J, Aubert JD, Schlegel‐Haueter S, Nicod LP. 1995. GRO alpha and interleukin‐8 in Pneumocystis carinii or bacterial pneumonia and adult respiratory distress syndrome. Am J Respir Crit Care Med 152: 1549–1554. [PubMed] [Google Scholar]
  • Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, Wang PH, Chen YT, Chang C. 2003. Interleukin‐6 differentially regulates androgen receptor transactivation via PI3K‐Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun 305: 462–469. [PubMed] [Google Scholar]
  • Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A. 2003. IL‐6 induces an anti‐inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4: 551–556. [PubMed] [Google Scholar]
  • Yoshimura A. 1998. The CIS family: Negative regulators of JAK‐STAT signaling. Cytokine Growth Factor Rev 9: 197–204. [PubMed] [Google Scholar]
  • Young DF, Didcock L, Goodbourn S, Randall RE. 2000. Paramyxoviridae use distinct virus‐specific mechanisms to circumvent the interferon response. Virology 269: 383–390. [PubMed] [Google Scholar]
  • Zhang Y, Li J, Zhan Y, Wu L, Yu X, Zhang W, Ye L, Xu S, Sun R, Wang Y, Lou J. 2004. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 72: 4410–4415. [PMC free article] [PubMed] [Google Scholar]
  • Zhao Z, Zhang F, Xu M, Huang K, Zhong W, Cai W, Yin Z, Huang S, Deng Z, Wei M, Xiong J, Hawkey PM. 2003. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol 52: 715–720. [PubMed] [Google Scholar]
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