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Conditional transgenic expression of TIR-domain-containing adaptor-inducing interferon-β (TRIF) in the adult mouse heart is protective in acute viral myocarditis

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Basic Research in Cardiology Aims and scope Submit manuscript

An Erratum to this article was published on 22 December 2011

An Erratum to this article was published on 22 December 2011

Abstract

TIR-domain-containing adaptor-inducing interferon-β (TRIF) plays a major role in Toll-like receptor 3 (TLR3) mediated signaling. Mice deficient in TLR3 and TRIF have been shown to be highly susceptible to enterovirus-induced myocardial injury. These mice have decreased production of antiviral cytokines and increased viral replication in the heart. Therefore, we hypothesized that conditional overexpression of TRIF would change cardiac myocyte susceptibility to virus infection by augmenting the antiviral response. We generated double-transgenic MHC-tTA/MHCtetO-TRIF mice (DT), with conditional cardiac-specific overexpression of TRIF. Naive DT mice had increased cardiac expression of antiviral cytokines and increased cellular infiltration but no alterations in cardiac function. DT mice were less susceptible to encephalomyocarditis virus (EMCV) infection and had a significantly lower viral load in the heart when compared to littermate (LM) and MHCtetO-TRIF (ST) mice. Histopathological examination showed that the severity of myocarditis was also attenuated in DT mice. Furthermore, the decreased virus titers in the DT mouse hearts led to less cardiac damage and better cardiac function when compared to LM and ST mice. Administration of doxycycline to DT mice suppressed the protective effects of TRIF overexpression in the heart. The findings of the present study establish the importance of cardiac-specific TRIF-mediated signaling in the heart in acute viral myocarditis and identify potentially important targets for diagnostic and therapeutic strategies.

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Abbreviations

ST:

Single trangenic MHC-tetO-TRIF mice

DT:

Double-transgenic MHC-tTA/MHCtetO-TRIF mice

cTnI:

Cardiac troponin I

References

  1. Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. J Infect Dis 183:1617–1624. doi:10.1086/320712

    Article  PubMed  CAS  Google Scholar 

  2. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185. doi:10.1016/j.pharmthera.2008.08.002

    Article  PubMed  CAS  Google Scholar 

  3. Chao W (2009) Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol 296:H1–H12. doi:10.1152/ajpheart.00995.2008

    Article  PubMed  CAS  Google Scholar 

  4. Deonarain R, Cerullo D, Fuse K, Liu PP, Fish EN (2004) Protective role for interferon-beta in coxsackievirus B3 infection. Circulation 110:3540–3543. doi:10.1161/01.CIR.0000136824.73458.20

    Article  PubMed  CAS  Google Scholar 

  5. Desai MS, Mariscalco MM, Tawil A, Vallejo JG, Smith CW (2008) Atherogenic diet-induced hepatitis is partially dependent on murine TLR4. J Leukoc Biol 83:1336–1344. doi:10.1189/jlb.0607390

    Article  PubMed  CAS  Google Scholar 

  6. Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, Steele R, Rose NR (2003) IL-12 receptor beta 1 and toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol 170:4731–4737. http://jimmunol.org/content/170/9/4731.full.pdf+html

    Google Scholar 

  7. Feldman AM, McNamara D (2000) Myocarditis. N Engl J Med 343:1388–1398. doi:10.1056/NEJM200011093431908

    Article  PubMed  CAS  Google Scholar 

  8. Fuse K, Chan G, Liu Y, Gudgeon P, Husain M, Chen M, Yeh WC, Akira S, Liu PP (2005) Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112:2276–2285. doi:10.1161/CIRCULATIONAHA.105.536433

    Article  PubMed  CAS  Google Scholar 

  9. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M (2006) Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA 103:8459–8464. doi:10.1073/pnas.0603082103

    Article  PubMed  CAS  Google Scholar 

  10. Gorbea C, Makar KA, Pauschinger M, Pratt G, Bersola JL, Varela J, David RM, Banks L, Huang CH, Li H, Schultheiss HP, Towbin JA, Vallejo JG, Bowles NE (2010) A role for toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy. J Biol Chem 285:23208–23223. doi:10.1074/jbc.M109.047464

    Article  PubMed  CAS  Google Scholar 

  11. Hardarson HS, Baker JS, Yang Z, Purevjav E, Huang CH, Alexopoulou L, Li N, Flavell R, Bowles NE, Vallejo JG (2006) Toll-like receptors 3 is an essential component of the innate stress response in virus-induced cardiac injury. Am J Physiol Heart Circ Physiol 292:H251–H258. doi:10.1152/ajpheart.00398.2006

    Article  PubMed  Google Scholar 

  12. Hennessy EJ, Parker AE, O’Neill LA (2010) Targeting toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9:293–307. doi:10.1038/nrd3203

    Article  PubMed  CAS  Google Scholar 

  13. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–748. doi:10.1038/nature01889

    Article  PubMed  CAS  Google Scholar 

  14. Huang CH, Vallejo JG, Kollias G, Mann DL (2009) Role of the innate immune system in acute viral myocarditis. Basic Res Cardiol 104:228–237. doi:10.1007/s00395-008-0765-5

    Article  PubMed  CAS  Google Scholar 

  15. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Sousa ReisE, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105. doi:10.1038/nature04734

    Article  PubMed  CAS  Google Scholar 

  16. Kleinbongard P, Heusch G, Schulz R (2010) TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314. doi:10.1016/j.pharmthera.2010.05.002

    Article  PubMed  CAS  Google Scholar 

  17. Knuefermann P, Sakata Y, Baker JS, Huang CH, Sekiguchi K, Hardarson HS, Takeuchi O, Akira S, Vallejo JG (2004) Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart. Circulation 110:3693–3698. doi:10.1161/01.CIR.0000143081.13042.04

    Article  PubMed  CAS  Google Scholar 

  18. Martinez J, Huang X, Yang Y (2008) Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. J Immunol 180:1592–1597. http://www.jimmunol.org.ezproxyhost.library.tmc.edu/content/180/3/1592.long

    Google Scholar 

  19. Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–298. doi:10.1016/S0092-8674(00)80412-2

    Article  PubMed  CAS  Google Scholar 

  20. Mersmann J, Habeck K, Latsch K, Zimmermann R, Jacoby C, Fischer JW, Hartmann C, Schrader J, Kirschning CJ, Zacharowski K (2010) Left ventricular dilation in toll-like receptor 2 deficient mice after myocardial ischemia/reperfusion through defective scar formation. Basic Res Cardiol. doi: 10.1007/s00395-010-0127-y

  21. Mukherjee A, Morosky SA, Delorme-Axford E, Dybdahl-Sissoko N, Oberste MS, Wang T, Coyne CB (2011) The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling. PLoS Pathog 7:e1001311. doi:10.1371/journal.ppat.1001311

    Article  PubMed  CAS  Google Scholar 

  22. Negishi H, Osawa T, Ogami K, Ouyang X, Sakaguchi S, Koshiba R, Yanai H, Seko Y, Shitara H, Bishop K, Yonekawa H, Tamura T, Kaisho T, Taya C, Taniguchi T, Honda K (2008) A critical link between toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc Natl Acad Sci USA 105:20446–20451. doi:10.1073/pnas.0810372105

    Article  PubMed  CAS  Google Scholar 

  23. Riad A, Westermann D, Zietsch C, Savvatis K, Becher PM, Bereswill S, Heimesaat MM, Lettau O, Lassner D, Dorner A, Poller W, Busch M, Felix SB, Schultheiss HP, Tschope C (2011) TRIF is a critical survival factor in viral cardiomyopathy. J Immunol 186:2561–2570. doi:10.4049/jimmunol.1002029

    Article  PubMed  CAS  Google Scholar 

  24. Satoh M, Nakamura M, Akatsu T, Iwasaka J, Shimoda Y, Segawa I, Hiramori K (2003) Expression of toll-like receptor 4 is associated with enteroviral replication in human myocarditis. Clin Sci (Lond) 104:577–584. doi:10.1042/CS20020263

    Article  CAS  Google Scholar 

  25. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci USA 107:1512–1517. doi:10.1073/pnas.0912986107

    Article  PubMed  CAS  Google Scholar 

  26. Seo SU, Kwon HJ, Song JH, Byun YH, Seong BL, Kawai T, Akira S, Kweon MN (2010) MyD88 signaling is indispensable for primary influenza A virus infection but dispensable for secondary infection. J Virol 84:12713–12722. doi:10.1128/JVI.01675-10

    Article  PubMed  CAS  Google Scholar 

  27. Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ, Agnew ML, Hampton CR, Rothnie CL, Spring DJ, Pohlman TH, Shimpo H, Verrier ED (2006) Inhibition of toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114:I270–I274. doi:10.1161/CIRCULATIONAHA.105.000901

    Article  PubMed  Google Scholar 

  28. Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, Yokoyama T, Kurabayashi M (2001) Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor-alpha. J Mol Cell Cardiol 33:1627–1635. doi:10.1006/jmcc.2001.1428

    Article  PubMed  CAS  Google Scholar 

  29. Valeur HS, Valen G (2009) Innate immunity and myocardial adaptation to ischemia. Basic Res Cardiol 104:22–32. doi:10.1007/s00395-008-0756-6

    Article  PubMed  CAS  Google Scholar 

  30. Voigt A, Bartel K, Egerer K, Trimpert C, Feist E, Gericke C, Kandolf R, Klingel K, Kuckelkorn U, Stangl K, Felix SB, Baumann G, Kloetzel PM, Staudt A (2010) Humoral anti-proteasomal autoimmunity in dilated cardiomyopathy. Basic Res Cardiol 105:9–18. doi:10.1007/s00395-009-0061-z

    Article  PubMed  CAS  Google Scholar 

  31. Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S, Maekawa N, Takatsu H, Fujiwara H, Sekikawa K, Seishima M (2001) Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: a study using mice lacking TNF-alpha. Circulation 103:743–749. http://circ.ahajournals.org/cgi/reprint/103/5/743

    Google Scholar 

  32. Wessely R, Klingel K, Knowlton KU, Kandolf R (2001) Cardioselective infection with coxsackievirus B3 requires intact type I interferon signaling—implications for mortality and early viral replication. Circulation 103:756–761. http://circ.ahajournals.org/cgi/reprint/103/5/743

    Google Scholar 

  33. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the toll-like receptor signaling. J Immunol 169:6668–6672. http://jimmunol.org/content/169/12/6668.full

    Google Scholar 

  34. 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. doi:10.1172/JCI16491

    PubMed  CAS  Google Scholar 

  35. Yuan J, Liu Z, Lim T, Zhang H, He J, Walker E, Shier C, Wang Y, Su Y, Sall A, McManus B, Yang D (2009) CXCL10 inhibits viral replication through recruitment of natural killer cells in coxsackievirus B3-induced myocarditis. Circ Res 104:628–638. doi:10.1161/CIRCRESAHA.108.192179

    Article  PubMed  CAS  Google Scholar 

  36. Zaragoza C, Ocampo C, Saura M, Leppo M, Wei XQ, Quick R, Moncada S, Liew FY, Lowenstein CJ (1998) The role of inducible nitric oxide synthase in the host response to Coxsackievirus myocarditis. Proc Natl Acad Sci USA 95:2469–2474. doi:10.1073/pnas.95.5.2469

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by grants HL083426 and HL091223 from the National Institutes of Health. We thank, Douglas L. Mann, MD for his critical review of the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, 1102 Bates Street, FC 430.09, Houston, TX, 77030, USA

    Zhaohui Xu, Moreshwar Desai, Joseph Philip & Jesus G. Vallejo

  2. Sections of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas

    Zhaohui Xu & Jesus G. Vallejo

  3. Critical Care Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA

    Moreshwar Desai & Joseph Philip

  4. Department of Medicine, Winters Center for Heart Failure Research, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA

    Natarajan Sivsubramanian

  5. Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, USA

    Neil E. Bowles

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  1. Zhaohui Xu
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  2. Moreshwar Desai
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  6. Jesus G. Vallejo
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Correspondence to Jesus G. Vallejo.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00395-011-0234-4

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Xu, Z., Desai, M., Philip, J. et al. Conditional transgenic expression of TIR-domain-containing adaptor-inducing interferon-β (TRIF) in the adult mouse heart is protective in acute viral myocarditis. Basic Res Cardiol 106, 1159–1171 (2011). https://doi.org/10.1007/s00395-011-0226-4

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