Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis

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Several highly pathogenic viruses encode small transmembrane proteins with ion-conduction properties named viroporins. Viroporins are generally involved in virus production and maturation processes, which many times are achieved by altering the ion homeostasis of cell organelles. Cells have evolved mechanisms to sense these imbalances in ion concentrations as a danger signal, and consequently trigger the innate immune system. Recently, it has been demonstrated that viroporins are inducers of cytosolic macromolecular complexes named inflammasomes that trigger the activation of key inflammatory cytokines such as IL-1β. The repercussions of this system in viral pathogenesis or disease outcome are currently being explored. SARS-CoV infection induces an uncontrolled inflammatory response leading to pulmonary damage, edema accumulation, severe hypoxemia and eventually death. In this study, we report that SARS-CoV E protein ion channel activity is a determinant of virulence, as the elimination of this function attenuated the virus, reducing the harmful inflammatory cytokine burst produced after infection, in which inflammasome activation plays a critical role. This led to less pulmonary damage and to disease resolution. These novel findings may be of relevance for other viral infections and can possibly be translated in order to find therapies for their associated diseases.

Vyšlo v časopise: Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004077
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004077

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Zdroje

1. PerlmanS, NetlandJ (2009) Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7: 439–450.

2. RotaPA, ObersteMS, MonroeSS, NixWA, CampganoliR, et al. (2003) Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300: 1394–1399.

3. DrostenC, GuntherS, PreiserW, van der WerfS, BrodtHR, et al. (2003) Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348: 1967–1976.

4. PyrcK, BerkhoutB, van der HoekL (2007) The novel human coronaviruses NL63 and HKU1. J Virol 81: 3051–3057.

5. ZakiAM, van BoheemenS, BestebroerTM, OsterhausAD, FouchierRA (2012) Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367: 1814–1820.

6. DanielssonN, CatchpoleM (2012) Novel coronavirus associated with severe respiratory disease: case definition and public health measures. Euro Surveill 17: 20282.

7. AssiriA, McGeerA, PerlTM, PriceCS, Al RabeeahAA, et al. (2013) Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med 369 ((5)) 407–16 doi:10.1056/NEJMoa1306742

8. MullerMA, PaweskaJT, LemanPA, DrostenC, GrywnaK, et al. (2007) Coronavirus antibodies in African bat species. Emerg Infect Dis 13: 1367–1370.

9. ChuDK, PeirisJS, ChenH, GuanY, PoonLL (2008) Genomic characterizations of bat coronaviruses (1A, 1B and HKU8) and evidence for co-infections in Miniopterus bats. J Gen Virol 89: 1282–1287.

10. DrexlerJF, Gloza-RauschF, GlendeJ, CormanVM, MuthD, et al. (2010) Genomic characterization of severe acute respiratory syndrome-related coronavirus in European bats and classification of coronaviruses based on partial RNA-dependent RNA polymerase gene sequences. J Virol 84: 11336–11349.

11. QuanPL, FirthC, StreetC, HenriquezJA, PetrosovA, et al. (2010) Identification of a severe acute respiratory syndrome coronavirus-like virus in a leaf-nosed bat in Nigeria. MBio 1: e00208–00210.

12. AnnanA, BaldwinHJ, CormanVM, KloseSM, OwusuM, et al. (2013) Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and Europe. Emerg Infect Dis 19: 456–459.

13. FalconA, Vazquez-MoronS, CasasI, AznarC, RuizG, et al. (2011) Detection of alpha and betacoronaviruses in multiple Iberian bat species. Arch Virol 156: 1883–1890.

14. Enjuanes L, Gorbalenya AE, de Groot RJ, Cowley JA, Ziebuhr J, et al.. (2008) The Nidovirales. In: Mahy BWJ, Van Regenmortel M, Walker P, Majumder-Russell D, editors. Encyclopedia of Virology, Third Edition. Oxford: Elsevier Ltd. pp. 419–430.

15. Nieto-TorresJL, DediegoML, AlvarezE, Jimenez-GuardenoJM, Regla-NavaJA, et al. (2011) Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein. Virology 415: 69–82.

16. DeDiegoML, AlvarezE, AlmazanF, RejasMT, LamirandeE, et al. (2007) A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. J Virol 81: 1701–1713.

17. MaedaJ, RepassJF, MaedaA, MakinoS (2001) Membrane topology of coronavirus E protein. Virology 281: 163–169.

18. RaamsmanMJB, LockerJK, de HoogeA, de VriesAAF, GriffithsG, et al. (2000) Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. J Virol 74: 2333–2342.

19. OrtegoJ, EscorsD, LaudeH, EnjuanesL (2002) Generation of a replication-competent, propagation-deficient virus vector based on the transmissible gastroenteritis coronavirus genome. J Virol 76: 11518–11529.

20. OrtegoJ, CerianiJE, PatinoC, PlanaJ, EnjuanesL (2007) Absence of E protein arrests transmissible gastroenteritis coronavirus maturation in the secretory pathway. Virology 368: 296–308.

21. AlmazanF, DediegoML, SolaI, ZunigaS, Nieto-TorresJL, et al. (2013) Engineering a replication-competent, propagation-defective Middle East respiratory syndrome coronavirus as a vaccine candidate. MBio 4: e00650–00613.

22. KuoL, MastersPS (2003) The small envelope protein E is not essential for murine coronavirus replication. J Virol 77: 4597–4608.

23. DeDiegoML, PeweL, AlvarezE, RejasMT, PerlmanS, et al. (2008) Pathogenicity of severe acute respiratory coronavirus deletion mutants in hACE-2 transgenic mice. Virology 376: 379–389.

24. LamirandeEW, DeDiegoML, RobertsA, JacksonJP, AlvarezE, et al. (2008) A live attenuated SARS coronavirus is immunogenic and efficacious in golden Syrian hamsters. J Virol 82: 7721–7724.

25. NetlandJ, DeDiegoML, ZhaoJ, FettC, AlvarezE, et al. (2010) Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease. Virology 399: 120–128.

26. FettC, DeDiegoML, Regla-NavaJA, EnjuanesL, PerlmanS (2013) Complete protection against severe acute respiratory syndrome coronavirus-mediated lethal respiratory disease in aged mice by immunization with a mouse-adapted virus lacking E protein. J Virol 87: 6551–6559.

27. DediegoML, Nieto-TorresJL, Regla-NavaJA, Jimenez-GuardenoJM, Fernandez-DelgadoR, et al. (2013) Inhibition of NF-kappaB mediated inflammation in severe acute respiratory syndome coronavirus-infected mice increases survival. J Virol 88 ((2)) 913–24 doi10.1128/JVI.02576-02513.

28. DeDiegoML, Nieto-TorresJL, Jimenez-GuardenoJM, Regla-NavaJA, AlvarezE, et al. (2011) Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis. PLoS pathog 7: e1002315.

29. TorresJ, ParthasarathyK, LinX, SaravananR, LiuDX (2006) Model of a putative pore: the pentameric alpha-helical bundle of SARS coronavirus E protein in lipid bilayers. Biophys J 91: 938–947.

30. PervushinK, TanE, ParthasarathyK, LinX, JiangFL, et al. (2009) Structure and inhibition of the SARS coronavirus envelope protein ion channel. PLoS Pathog 5: e1000511.

31. WilsonL, McKinlayC, GageP (2004) SARS coronavirus E protein forms cation-selective ion channels. Virology 330: 322–331.

32. ParthasarathyK, NgL, LinX, LiuDX, PervushinK, et al. (2008) Structural flexibility of the pentameric SARS coronavirus envelope protein ion channel. Biophys J 95: 39–41.

33. WilsonL, GageP, EwartG (2006) Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication. Virology 353: 294–306.

34. Verdia-BaguenaC, Nieto-TorresJL, AlcarazA, DediegoML, TorresJ, et al. (2012) Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids. Virology 432: 485–494.

35. TorresJ, MaheswariU, ParthasarathyK, NgL, LiuDX, et al. (2007) Conductance and amantadine binding of a pore formed by a lysine-flanked transmembrane domain of SARS coronavirus envelope protein. Protein Sci 16: 2065–2071.

36. Verdia-BaguenaC, Nieto-TorresJL, AlcarazA, DediegoML, EnjuanesL, et al. (2013) Analysis of SARS-CoV E protein ion channel activity by tuning the protein and lipid charge. Biochim Biophys Acta 1828: 2026–2031.

37. YeY, HogueBG (2007) Role of the coronavirus E viroporin protein transmembrane domain in virus assembly. J Virol 81: 3597–3607.

38. KuoL, HurstKR, MastersPS (2006) Exceptional flexibility in the sequence requirements for coronavirus small envelope protein (E) function. J Virol 81: 2249–2262.

39. RuchTR, MachamerCE (2011) The hydrophobic domain of infectious bronchitis virus E protein alters the host secretory pathway and is important for release of infectious virus. J Virol 85: 675–685.

40. RuchTR, MachamerCE (2012) A single polar residue and distinct membrane topologies impact the function of the infectious bronchitis coronavirus E protein. PLoS Pathog 8: e1002674.

41. LuW, ZhengBJ, XuK, SchwarzW, DuL, et al. (2006) Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc Natl Acad Sci USA 103: 12540–12545.

42. ChenCC, KrugerJ, SramalaI, HsuHJ, HenkleinP, et al. (2011) ORF8a of SARS-CoV forms an ion channel: experiments and molecular dynamics simulations. Biochim Biophys Acta 1808: 572–579.

43. ZhangR, WangK, LvW, YuW, XieS, et al. (2013) The ORF4a protein of human coronavirus 229E functions as a viroporin that regulates viral production. Biochim Biophys Acta 1838 ((4)) 1088–95 doi 10.1016j.bbamem.2013.1007.1025/j.bbamem.2013.1007.1025

44. NievaJL, MadanV, CarrascoL (2012) Viroporins: structure and biological functions. Nat Rev Microbiol 10: 563–574.

45. PintoLH, HolsingerLJ, LambRA (1992) Influenza virus M2 protein has ion channel activity. Cell 69: 517–528.

46. EwartGD, SutherlandT, GagePW, CoxGB (1996) The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels. J Virol 70: 7108–7115.

47. PavlovicD, NevilleDC, ArgaudO, BlumbergB, DwekRA, et al. (2003) The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci USA 100: 6104–6108.

48. de JongAS, VischHJ, de MattiaF, van DommelenMM, SwartsHG, et al. (2006) The coxsackievirus 2B protein increases efflux of ions from the endoplasmic reticulum and Golgi, thereby inhibiting protein trafficking through the Golgi. J Biol Chem 281: 14144–14150.

49. HenkelM, MitznerD, HenkleinP, Meyer-AlmesFJ, MoroniA, et al. (2010) The proapoptotic influenza A virus protein PB1-F2 forms a nonselective ion channel. PLoS One 5: e11112.

50. CampanellaM, de JongAS, LankeKW, MelchersWJ, WillemsPH, et al. (2004) The coxsackievirus 2B protein suppresses apoptotic host cell responses by manipulating intracellular Ca2+ homeostasis. J Biol Chem 279: 18440–18450.

51. WozniakAL, GriffinS, RowlandsD, HarrisM, YiM, et al. (2010) Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS Pathog 6: e1001087.

52. IchinoheT, PangIK, IwasakiA (2010) Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol 11: 404–410.

53. McAuleyJL, TateMD, MacKenzie-KludasCJ, PinarA, ZengW, et al. (2013) Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. PLoS Pathog 9: e1003392.

54. SakaguchiT, LeserGP, LambRA (1996) The ion channel activity of the influenza virus M2 protein affects transport through the Golgi apparatus. J Cell Biol 133: 733–747.

55. de JongAS, de MattiaF, Van DommelenMM, LankeK, MelchersWJ, et al. (2008) Functional analysis of picornavirus 2B proteins: effects on calcium homeostasis and intracellular protein trafficking. J Virol 82: 3782–3790.

56. CornellCT, KiossesWB, HarkinsS, WhittonJL (2007) Coxsackievirus B3 proteins directionally complement each other to downregulate surface major histocompatibility complex class I. J Virol 81: 6785–6797.

57. TriantafilouK, KarS, VakakisE, KotechaS, TriantafilouM (2013) Human respiratory syncytial virus viroporin SH: a viral recognition pathway used by the host to signal inflammasome activation. Thorax 68: 66–75.

58. ZhangK, HouQ, ZhongZ, LiX, ChenH, et al. (2013) Porcine reproductive and respiratory syndrome virus activates inflammasomes of porcine alveolar macrophages via its small envelope protein E. Virology 442: 156–162.

59. ItoM, YanagiY, IchinoheT (2012) Encephalomyocarditis virus viroporin 2B activates NLRP3 inflammasome. PLoS Pathog 8: e1002857.

60. RobertsA, DemingD, PaddockCD, ChengA, YountB, et al. (2007) A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog 3: 23–37.

61. Regla-NavaJA, Jimenez-GuardenoJM, Nieto-TorresJL, GallagherTM, EnjuanesL, et al. (2013) The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines. J Virol Methods 193: 639–646.

62. MeduriGU, HeadleyS, KohlerG, StentzF, TolleyE, et al. (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107: 1062–1073.

63. TisoncikJR, KorthMJ, SimmonsCP, FarrarJ, MartinTR, et al. (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76: 16–32.

64. MartinonF, PetrilliV, MayorA, TardivelA, TschoppJ (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237–241.

65. WatanabeT, WatanabeS, ItoH, KidaH, KawaokaY (2001) Influenza A virus can undergo multiple cycles of replication without M2 ion channel activity. J Virol 75: 5656–5662.

66. TakedaM, PekoszA, ShuckK, PintoLH, LambRA (2002) Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture. J Virol 76: 1391–1399.

67. BukreyevA, WhiteheadSS, MurphyBR, CollinsPL (1997) Recombinant respiratory syncytial virus from which the entire SH gene has been deleted grows efficiently in cell culture and exhibits site-specific attenuation in the respiratory tract of the mouse. J Virol 71: 8973–8982.

68. WhiteheadSS, BukreyevA, TengMN, FirestoneCY, St ClaireM, et al. (1999) Recombinant respiratory syncytial virus bearing a deletion of either the NS2 or SH gene is attenuated in chimpanzees. J Virol 73: 3438–3442.

69. WatanabeS, WatanabeT, KawaokaY (2009) Influenza A virus lacking M2 protein as a live attenuated vaccine. J Virol 83: 5947–5950.

70. GladueDP, HolinkaLG, LargoE, Fernandez SainzI, CarrilloC, et al. (2012) Classical swine fever virus p7 protein is a viroporin involved in virulence in swine. J Virol 86: 6778–6791.

71. GrahamRL, DonaldsonEF, BaricRS (2013) A decade after SARS: strategies for controlling emerging coronaviruses. Nat Rev Microbiol 11: 836–848.

72. MatthayMA, ZemansRL (2011) The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 6: 147–163.

73. HollenhorstMI, RichterK, FroniusM (2011) Ion transport by pulmonary epithelia. J Biomed Biotechnol 2011: 174306.

74. RockxB, BaasT, ZornetzerGA, HaagmansB, SheahanT, et al. (2009) Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 83: 7062–7074.

75. PuginJ, RicouB, SteinbergKP, SuterPM, MartinTR (1996) Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am J Respir Crit Care Med 153: 1850–1856.

76. GrommesJ, SoehnleinO (2011) Contribution of neutrophils to acute lung injury. Mol Med 17: 293–307.

77. dos SantosG, KutuzovMA, RidgeKM (2012) The inflammasome in lung diseases. Am J Physiol Lung Cell Mol Physiol 303: L627–633.

78. StrowigT, Henao-MejiaJ, ElinavE, FlavellR (2012) Inflammasomes in health and disease. Nature 481: 278–286.

79. WangCH, LiuCY, WanYL, ChouCL, HuangKH, et al. (2005) Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res 6: 42.

80. FriemanMB, ChenJ, MorrisonTE, WhitmoreA, FunkhouserW, et al. (2010) SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6: e1000849.

81. SheahanT, MorrisonTE, FunkhouserW, UematsuS, AkiraS, et al. (2008) MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog 4: e1000240.