1887

Abstract

Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNλs) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3- and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A, indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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2016-06-01
2021-07-29
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References

  1. Andrejeva J., Childs K. S., Young D. F., Carlos T. S., Stock N., Goodbourn S., Randall R. E. 2004; The V proteins of paramyxo viruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci U S A 101:17264–17269 [View Article][PubMed]
    [Google Scholar]
  2. Barral P. M., Morrison J. M., Drahos J., Gupta P., Sarkar D., Fisher P. B., Racaniello V. R. 2007; MDA-5 is cleaved in polio virus-infected cells. J Virol 81:3677–3684 [View Article][PubMed]
    [Google Scholar]
  3. Chapman N. M., Kim K. S. 2008; Persistent coxsackievirus infection: enterovirus persistence in chronic myocarditis and dilated cardiomyopathy. Curr Top Microbiol Immunol 323:275–292[PubMed]
    [Google Scholar]
  4. Dauletbaev N., Cammisano M., Herscovitch K., Lands L. C. 2015; Stimulation of the RIG-I/MAVS pathway by polyinosinic: acid upregulates IFN-β in airway epithelial cells with minimal costimulation of IL-8. J Immunol 195:2829–2841 [View Article][PubMed]
    [Google Scholar]
  5. de Weerd N. A., Nguyen T. 2012; The interferons and their receptors–distribution and regulation. Immunol Cell Biol 90:483–491 [View Article][PubMed]
    [Google Scholar]
  6. Díaz-San Segundo F., Weiss M., Perez-Martín E., Koster M. J., Zhu J., Grubman M. J., de los Santos T. 2011; Antiviral activity of bovine type III interferon against foot-and-mouth disease virus. Arch Virol 413:283–292 [View Article][PubMed]
    [Google Scholar]
  7. Ding Q., Huang B., Lu J., Liu Y. J., Zhong J. 2012; Hepatitis C virus NS3/4A protease blocks IL-28 production. Eur J Immunol 42:2374–2382 [View Article][PubMed]
    [Google Scholar]
  8. Drahos J., Racaniello V. R. 2009; Cleavage of IPS-1 in cells infected with human rhinovirus. J Virol 83:11581–11587 [View Article][PubMed]
    [Google Scholar]
  9. Egli A., Santer D. M., O’Shea D., Tyrrell D. L., Houghton M. 2014; The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections. Emerg Microbes Infect 3:e51 [View Article][PubMed]
    [Google Scholar]
  10. Feng Q., Langereis M. A., Lork M., Nguyen M., Hato S. V., Lanke K., Emdad L., Bhoopathi P., Fisher P. B., other authors. 2014a; Enterovirus 2Apro targets MDA5 and MAVS in infected cells. J Virol 88:3369–3378 [View Article][PubMed]
    [Google Scholar]
  11. Feng Q., Langereis M. A., van Kuppeveld F. J. 2014b; Induction and suppression of innate antiviral responses by picornaviruses. Cytokine Growth Factor Rev 25:577–585 [View Article][PubMed]
    [Google Scholar]
  12. Gitlin L., Barchet W., Gilfillan S., Cella M., Beutler B., Flavell R. A., Diamond M. S., Colonna M. 2006; Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci U S A 103:8459–8464 [View Article][PubMed]
    [Google Scholar]
  13. Hermant P., Michiels T. 2014; Interferon-λ in the context of viral infections: production, response and therapeutic implications. J Innate Immun 6:563–574 [View Article][PubMed]
    [Google Scholar]
  14. Hoffmann H. H., Schneider W. M., Rice C. M. 2015; Interferons and viruses: an evolutionary arms race of molecular interactions. Mod Trends Immunol 36:124–138 [View Article][PubMed]
    [Google Scholar]
  15. Huber S. 2008; Host immune responses to coxsackievirus B3. Curr Top Microbiol Immunol 323:199–221[PubMed]
    [Google Scholar]
  16. Hühn M. H., Hultcrantz M., Lind K., Ljunggren H. G., Malmberg K. J., Flodström-Tullberg M. 2008; IFN-gamma production dominates the early human natural killer cell response to Coxsackievirus infection. Cell Microbiol 10:426–436 [View Article][PubMed]
    [Google Scholar]
  17. Hühn M. H., McCartney S. A., Lind K., Svedin E., Colonna M., Flodström-Tullberg M. 2010; Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after coxsackievirus infection. Virology 401:42–48 [View Article][PubMed]
    [Google Scholar]
  18. Jensen S., Thomsen A. R. 2012; Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol 86:2900–2910 [View Article][PubMed]
    [Google Scholar]
  19. Joachims M., Van Breugel P. C., Lloyd R. E. 1999; Cleavage of poly(A)-binding protein by enterovirus proteases concurrent with inhibition of translation in vitro. J Virol 73:718–727[PubMed]
    [Google Scholar]
  20. Knip M., Simell O. 2012; Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med 2:a007690 [View Article][PubMed]
    [Google Scholar]
  21. Kotenko S. V. 2011; IFN-λs. Curr Opin Immunol 23:583–590 [View Article][PubMed]
    [Google Scholar]
  22. Kräusslich H. G., Nicklin M. J., Toyoda H., Etchison D., Wimmer E. 1987; Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220. J Virol 61:2711–2718[PubMed]
    [Google Scholar]
  23. Lazear H. M., Nice T. J., Diamond M. S. 2015; Interferon-λ: immune functions at barrier surfaces and beyond. Immunity 43:15–28 [View Article][PubMed]
    [Google Scholar]
  24. Lei X., Sun Z., Liu X., Jin Q., He B., Wang J. 2011; Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol 85:8811–8818 [View Article][PubMed]
    [Google Scholar]
  25. Li M., Liu X., Zhou Y., Su S. B. 2009; Interferon-λ: the modulators of antivirus, antitumor, and immune responses. J Leukoc Biol 86:23–32 [View Article][PubMed]
    [Google Scholar]
  26. Lin R., Mamane Y., Hiscott J. 1999; Structural and functional analysis of interferon regulatory factor 3: localization of the transactivation and autoinhibitory domains. Mol Cell Biol 19:2465–2474 [View Article][PubMed]
    [Google Scholar]
  27. Lind K., Hühn M. H., Flodström-Tullberg M. 2012; Immunology in the clinic review series; focus on type 1 diabetes and viruses: the innate immune response to enteroviruses and its possible role in regulating type 1 diabetes. Clin Exp Immunol 168:30–38 [View Article][PubMed]
    [Google Scholar]
  28. Lind K., Richardson S. J., Leete P., Morgan N. G., Korsgren O., Flodström-Tullberg M. 2013; Induction of an antiviral state and attenuated coxsackievirus replication in type III interferon-treated primary human pancreatic islets. J Virol 87:7646–7654 [View Article][PubMed]
    [Google Scholar]
  29. Lind K., Svedin E., Utorova R., Stone V. M., Flodström-Tullberg M. 2014; Type III interferons are expressed by coxsackievirus-infected human primary hepatocytes and regulate hepatocyte permissiveness to infection. Clin Exp Immunol 177:687–695 [View Article][PubMed]
    [Google Scholar]
  30. Liu S., Cai X., Wu J., Cong Q., Chen X., Li T., Du F., Ren J., Wu Y. T., other authors. 2015; Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347:aaa2630 [View Article][PubMed]
    [Google Scholar]
  31. Mukherjee A., Morosky S. A., Delorme-Axford E., Dybdahl-Sissoko N., Oberste M. S., Wang T., Coyne C. B. 2011; The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling. PLoS Pathog 7:e1001311 [View Article][PubMed]
    [Google Scholar]
  32. Negishi H., Osawa T., Ogami K., Ouyang X., Sakaguchi S., Koshiba R., Yanai H., Seko Y., Shitara H., other authors. 2008; A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc Natl Acad Sci U S A 105:20446–20451 [View Article][PubMed]
    [Google Scholar]
  33. Pallansch M. A., Roos R. P. 2007; Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In Fields Virology, 5th edn. pp. 839893 Edited by D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman, S. E. Straus. Philadelphia, PA: Lippincott Williams & Wilkins;
    [Google Scholar]
  34. Pott J., Mahlakõiv T., Mordstein M., Duerr C. U., Michiels T., Stockinger S., Staeheli P., Hornef M. W. 2011; IFN-lambda determines the intestinal epithelial antiviral host defense. Proc Natl Acad Sci U S A 108:7944–7949 [View Article][PubMed]
    [Google Scholar]
  35. Rebsamen M., Meylan E., Curran J., Tschopp J. 2008; The anti viral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ 15:1804–1811 [View Article][PubMed]
    [Google Scholar]
  36. Richardson S. J., Leete P., Dhayal S., Russell M. A., Oikarinen M., Laiho J. E., Svedin E., Lind K., Rosenling T., Morgan N. G., other authors. 2014; Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas. Diabetologia 57:392–401 [View Article][PubMed]
    [Google Scholar]
  37. Servant M. J., ten Oever B., LePage C., Conti L., Gessani S., Julkunen I., Lin R., Hiscott J. 2001; Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3. J Biol Chem 276:355–363 [View Article][PubMed]
    [Google Scholar]
  38. Stetson D. B., Medzhitov R. 2006; Type I interferons in host defense. Immunity 25:373–381 [View Article][PubMed]
    [Google Scholar]
  39. Taylor K. E., Mossman K. L. 2013; Recent advances in understanding viral evasion of type I interferon. Immunology 138:190–197 [View Article][PubMed]
    [Google Scholar]
  40. Wang D., Fang L., Liu L., Zhong H., Chen Q., Luo R., Liu X., Zhang Z., Chen H., Xiao S. 2011; Foot-and-mouth disease virus (FMDV) leader proteinase negatively regulates the porcine interferon-λ1 pathway. Mol Immunol 49:407–412 [View Article][PubMed]
    [Google Scholar]
  41. Wang B., Xi X., Lei X., Zhang X., Cui S., Wang J., Jin Q., Zhao Z. 2013; Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog 9:e1003231 [View Article][PubMed]
    [Google Scholar]
  42. Wang Y., Li J., Wang X., Ye L., Zhou Y., Thomas R. M., Ho W. 2014; Hepatitis C virus impairs TLR3 signaling and inhibits IFN-λ 1 expression in human hepatoma cell line. Innate Immun 20:3–11 [View Article][PubMed]
    [Google Scholar]
  43. White J. P., Cardenas A. M., Marissen W. E., Lloyd R. E. 2007; Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase. Cell Host Microbe 2:295–305 [View Article][PubMed]
    [Google Scholar]
  44. Xiang Z., Li L., Lei X., Zhou H., Zhou Z., He B., Wang J. 2014; Enterovirus 68 3C protease cleaves TRIF to attenuate antiviral responses mediated by Toll-like receptor 3. J Virol 88:6650–6659 [View Article][PubMed]
    [Google Scholar]
  45. Yeung W. C., Rawlinson W. D., Craig M. E. 2011; Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35 [View Article][PubMed]
    [Google Scholar]
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