Marburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virus

English version České info

Previous studies have demonstrated that Marburg viruses (MARV) and Ebola viruses (EBOV) inhibit interferon (IFN)-α/β signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits IFNα/β induced tyrosine phosphorylation of STAT1 and STAT2. MARV infection is now demonstrated to inhibit not only IFNα/β but also IFNγ-induced STAT phosphorylation and to inhibit the IFNα/β and IFNγ-induced tyrosine phosphorylation of upstream Janus (Jak) family kinases. Surprisingly, the MARV matrix protein VP40, not the MARV VP24 protein, has been identified to antagonize Jak and STAT tyrosine phosphorylation, to inhibit IFNα/β or IFNγ-induced gene expression and to inhibit the induction of an antiviral state by IFNα/β. Global loss of STAT and Jak tyrosine phosphorylation in response to both IFNα/β and IFNγ is reminiscent of the phenotype seen in Jak1-null cells. Consistent with this model, MARV infection and MARV VP40 expression also inhibit the Jak1-dependent, IL-6-induced tyrosine phosphorylation of STAT1 and STAT3. Finally, expression of MARV VP40 is able to prevent the tyrosine phosphorylation of Jak1, STAT1, STAT2 or STAT3 which occurs following over-expression of the Jak1 kinase. In contrast, MARV VP40 does not detectably inhibit the tyrosine phosphorylation of STAT2 or Tyk2 when Tyk2 is over-expressed. Mutation of the VP40 late domain, essential for efficient VP40 budding, has no detectable impact on inhibition of IFN signaling. This study shows that MARV inhibits IFN signaling by a mechanism different from that employed by the related EBOV. It identifies a novel function for the MARV VP40 protein and suggests that MARV may globally inhibit Jak1-dependent cytokine signaling.

Vyšlo v časopise: Marburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virus. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000721
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000721

Souhrn

Zdroje

1. BrayM

GeisbertTW

2005 Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int J Biochem Cell Biol 37 1560 1566

2. ToughDF

2004 Type I interferon as a link between innate and adaptive immunity through dendritic cell stimulation. Leuk Lymphoma 45 257 264

3. BironCA

CousensLP

RuzekMC

SuHC

Salazar-MatherTP

1998 Early cytokine responses to viral infections and their roles in shaping endogenous cellular immunity. Adv Exp Med Biol 452 143 149

4. PlataniasLC

2005 Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5 375 386

5. MullerM

BriscoeJ

LaxtonC

GuschinD

ZiemieckiA

1993 The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 366 129 135

6. YangCH

MurtiA

ValentineWJ

DuZ

PfefferLM

2005 Interferon alpha activates NF-kappaB in JAK1-deficient cells through a TYK2-dependent pathway. J Biol Chem 280 25849 25853

7. RodigSJ

MerazMA

WhiteJM

LampePA

RileyJK

1998 Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93 373 383

8. GuschinD

RogersN

BriscoeJ

WitthuhnB

WatlingD

1995 A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. Embo J 14 1421 1429

9. MühlbergerE

2007 Filovirus replication and transcription. Future Virology 2 205 215

10. LicataJM

Simpson-HolleyM

WrightNT

HanZ

ParagasJ

2003 Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. J Virol 77 1812 1819

11. NodaT

EbiharaH

MuramotoY

FujiiK

TakadaA

2006 Assembly and budding of Ebolavirus. PLoS Pathog 2 e99 doi:10.1371/journal.ppat.0020099

12. YamayoshiS

NodaT

EbiharaH

GotoH

MorikawaY

2008 Ebola virus matrix protein VP40 uses the COPII transport system for its intracellular transport. Cell Host Microbe 3 168 177

13. KolesnikovaL

StreckerT

MoritaE

ZieleckiF

MittlerE

2009 Vacuolar protein sorting pathway contributes to the release of Marburg virus. J Virol 83 2327 2337

14. TimminsJ

SchoehnG

Ricard-BlumS

ScianimanicoS

VernetT

2003 Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4. J Mol Biol 326 493 502

15. SwensonDL

WarfieldKL

KuehlK

LarsenT

HeveyMC

2004 Generation of Marburg virus-like particles by co-expression of glycoprotein and matrix protein. FEMS Immunol Med Microbiol 40 27 31

16. BavariS

BosioCM

WiegandE

RuthelG

WillAB

2002 Lipid raft microdomains: a gateway for compartmentalized trafficking of Ebola and Marburg viruses. J Exp Med 195 593 602

17. Martin-SerranoJ

ZangT

BieniaszPD

2001 HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat Med 7 1313 1319

18. UrataS

NodaT

KawaokaY

MorikawaS

YokosawaH

2007 Interaction of Tsg101 with Marburg virus VP40 depends on the PPPY motif, but not the PT/SAP motif as in the case of Ebola virus, and Tsg101 plays a critical role in the budding of Marburg virus-like particles induced by VP40, NP, and GP. J Virol 81 4895 4899

19. BambergS

KolesnikovaL

MöllerP

KlenkHD

BeckerS

2005 VP24 of Marburg virus influences formation of infectious particles. J Virol 79 13421 13433

20. HanZ

BoshraH

SunyerJO

ZwiersSH

ParagasJ

2003 Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding. J Virol 77 1793 1800

21. LicataJM

JohnsonRF

HanZ

HartyRN

2004 Contribution of ebola virus glycoprotein, nucleoprotein, and VP24 to budding of VP40 virus-like particles. J Virol 78 7344 7351

22. HoenenT

GrosethA

KolesnikovaL

TheriaultS

EbiharaH

2006 Infection of naive target cells with virus-like particles: implications for the function of ebola virus VP24. J Virol 80 7260 7264

23. NodaT

HalfmannP

SagaraH

KawaokaY

2007 Regions in Ebola virus VP24 that are important for nucleocapsid formation. J Infect Dis 196 Suppl 2 S247 250

24. VolchkovVE

ChepurnovAA

VolchkovaVA

TernovojVA

KlenkHD

2000 Molecular characterization of guinea pig-adapted variants of Ebola virus. Virology 277 147 155

25. EbiharaH

TakadaA

KobasaD

JonesS

NeumannG

2006 Molecular determinants of Ebola virus virulence in mice. PLoS Pathog 2 e73 doi:10.1371/journal.ppat.0020073

26. KaletskyRL

FrancicaJR

Agrawal-GamseC

BatesP

2009 Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci U S A 106 2886 2891

27. GuptaM

MahantyS

AhmedR

RollinPE

2001 Monocyte-derived human macrophages and peripheral blood mononuclear cells infected with ebola virus secrete MIP-1alpha and TNF-alpha and inhibit poly-IC-induced IFN-alpha in vitro. Virology 284 20 25

28. HarcourtBH

SanchezA

OffermannMK

1999 Ebola virus selectively inhibits responses to interferons, but not to interleukin-1beta, in endothelial cells. J Virol 73 3491 3496

29. HartmanAL

LingL

NicholST

HibberdML

2008 Whole-genome expression profiling reveals that inhibition of host innate immune response pathways by Ebola virus can be reversed by a single amino acid change in the VP35 protein. J Virol 82 5348 5358

30. KashJC

MühlbergerE

CarterV

GroschM

PerwitasariO

2006 Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence. J Virol 80 3009 3020

31. BaslerCF

WangX

MühlbergerE

VolchkovV

ParagasJ

2000 The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Natl Acad Sci U S A 97 12289 12294

32. HartmanAL

TownerJS

NicholST

2004 A C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus. Virology 328 177 184

33. ReidSP

LeungLW

HartmanAL

MartinezO

ShawML

2006 Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J Virol 80 5156 5167

34. ReidSP

ValmasC

MartinezO

SanchezFM

BaslerCF

2007 Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1. J Virol 81 13469 13477

35. SanchezA

KileyMP

HollowayBP

AuperinDD

1993 Sequence analysis of the Ebola virus genome: organization, genetic elements, and comparison with the genome of Marburg virus. Virus Res 29 215 240

36. MühlbergerE

WeikM

VolchkovVE

KlenkHD

BeckerS

1999 Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J Virol 73 2333 2342

37. EnterleinS

SchmidtKM

SchümannM

ConradD

KrählingV

2009 The marburg virus 3′ noncoding region structurally and functionally differs from that of ebola virus. J Virol 83 4508 4519

38. SanchezA

TrappierSG

MahyBW

PetersCJ

NicholST

1996 The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc Natl Acad Sci U S A 93 3602 3607

39. VolchkovVE

BeckerS

VolchkovaVA

TernovojVA

KotovAN

1995 GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases. Virology 214 421 430

40. HuangY

XuL

SunY

NabelGJ

2002 The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein. Mol Cell 10 307 316

41. KolesnikovaL

MühlbergerE

RyabchikovaE

BeckerS

2000 Ultrastructural organization of recombinant Marburg virus nucleoprotein: comparison with Marburg virus inclusions. J Virol 74 3899 3904

42. MühlbergerE

2004 Genome organization, replication, and transcription of filoviruses.

H.-DFeldmann HaK

Ebola and Marburg viruses: Molecular and cellular biology Wymondham, Norfolk Horizon Scientific Press 1 12

43. WiesmannC

BarrKJ

KungJ

ZhuJ

ErlansonDA

2004 Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 11 730 737

44. ShawML

Garcia-SastreA

PaleseP

BaslerCF

2004 Nipah virus V and W proteins have a common STAT1-binding domain yet inhibit STAT1 activation from the cytoplasmic and nuclear compartments, respectively. J Virol 78 5633 5641

45. BrzozkaK

FinkeS

ConzelmannKK

2006 Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. J Virol 80 2675 2683

46. BestSM

MorrisKL

ShannonJG

RobertsonSJ

MitzelDN

2005 Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol 79 12828 12839

47. MatsusakaT

FujikawaK

NishioY

MukaidaN

MatsushimaK

1993 Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci U S A 90 10193 10197

48. KunschC

RosenCA

1993 NF-kappa B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol 13 6137 6146

49. QuelleFW

ThierfelderW

WitthuhnBA

TangB

CohenS

1995 Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor. J Biol Chem 270 20775 20780

50. JahrlingPB

GeisbertTW

GeisbertJB

SwearengenJR

BrayM

1999 Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. J Infect Dis 179 Suppl 1 S224 234

51. TownerJS

KhristovaML

SealyTK

VincentMJ

EricksonBR

2006 Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola. J Virol 80 6497 6516

52. LeroyEM

KumulunguiB

PourrutX

RouquetP

HassaninA

2005 Fruit bats as reservoirs of Ebola virus. Nature 438 575 576

53. PourrutX

SourisM

TownerJS

RollinPE

NicholST

2009 Large serological survey showing cocirculation of Ebola and Marburg viruses in Gabonese bat populations, and a high seroprevalence of both viruses in Rousettus aegyptiacus. BMC Infect Dis 9 159

54. TownerJS

AmmanBR

SealyTK

CarrollSA

ComerJA

2009 Isolation of genetically diverse Marburg viruses from Egyptian fruit bats. PLoS Pathog 5 e1000536 doi:10.1371/journal.ppat.1000536

55. BarretteRW

MetwallySA

RowlandJM

XuL

ZakiSR

2009 Discovery of swine as a host for the Reston ebolavirus. Science 325 204 206

56. PanchalRG

BradfuteSB

PeyserBD

WarfieldKL

RuthelG

2009 Reduced levels of protein tyrosine phosphatase CD45 protect mice from the lethal effects of Ebola virus infection. Cell Host Microbe 6 162 173

57. XuD

QuCK

2008 Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci 13 4925 4932

58. BaslerCF

MikulasovaA

Martinez-SobridoL

ParagasJ

MühlbergerE

2003 The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J Virol 77 7945 7956

59. CardenasWB

LooYM

Gale MJr

HartmanAL

KimberlinCR

2006 Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J Virol 80 5168 5178

60. PrinsKC

CardenasWB

BaslerCF

2009 Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1. J Virol 83 3069 3077

61. HensleyLE

YoungHA

JahrlingPB

GeisbertTW

2002 Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol Lett 80 169 179

62. LanfordRE

GuerraB

LeeH

AverettDR

PfeifferB

2003 Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(i)-poly(c), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons. J Virol 77 1092 1104

63. MillerDM

RahillBM

BossJM

LairmoreMD

DurbinJE

1998 Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J Exp Med 187 675 683

64. CaignardG

GuerboisM

LabernardiereJL

JacobY

JonesLM

2007 Measles virus V protein blocks Jak1-mediated phosphorylation of STAT1 to escape IFN-alpha/beta signaling. Virology 368 351 362

65. HartyRN

BrownME

WangG

HuibregtseJ

HayesFP

2000 A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding. Proc Natl Acad Sci U S A 97 13871 13876

66. RuigrokRW

SchoehnG

DessenA

ForestE

VolchkovV

2000 Structural characterization and membrane binding properties of the matrix protein VP40 of Ebola virus. J Mol Biol 300 103 112

67. KolesnikovaL

RyabchikovaE

ShestopalovA

BeckerS

2007 Basolateral budding of Marburg virus: VP40 retargets viral glycoprotein GP to the basolateral surface. J Infect Dis 196 Suppl 2 S232 236

68. AhmedA

El KossiM

KarimM

RafteryA

El NahasAM

2003 Extracellular matrix changes following renal warm ischemic injury in rats. Transplant Proc 35 101 102

69. FerranMC

Lucas-LenardJM

1997 The vesicular stomatitis virus matrix protein inhibits transcription from the human beta interferon promoter. J Virol 71 371 377

70. BlackBL

LylesDS

1992 Vesicular stomatitis virus matrix protein inhibits host cell-directed transcription of target genes in vivo. J Virol 66 4058 4064

71. HerLS

LundE

DahlbergJE

1997 Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Science 276 1845 1848

72. YasudaJ

NakaoM

KawaokaY

ShidaH

2003 Nedd4 regulates egress of Ebola virus-like particles from host cells. J Virol 77 9987 9992

73. McCarthySE

JohnsonRF

ZhangYA

SunyerJO

HartyRN

2007 Role for amino acids 212KLR214 of Ebola virus VP40 in assembly and budding. J Virol 81 11452 11460

74. SakumaT

NodaT

UrataS

KawaokaY

YasudaJ

2009 Inhibition of Lassa and Marburg virus production by tetherin. J Virol 83 2382 2385

75. OkumuraA

PithaPM

HartyRN

2008 ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc Natl Acad Sci U S A 105 3974 3979

76. MalakhovaOA

ZhangDE

2008 ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J Biol Chem 283 8783 8787

77. ParkMS

ShawML

Munoz-JordanJ

CrosJF

NakayaT

2003 Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDV V protein and the Nipah virus V, W, and C proteins. J Virol 77 1501 1511

78. NiwaH

YamamuraK

MiyazakiJ

1991 Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108 193 199

79. RodriguezJJ

ParisienJP

HorvathCM

2002 Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation. J Virol 76 11476 11483

80. CiancanelliMJ

BaslerCF

2006 Mutation of YMYL in the Nipah virus matrix protein abrogates budding and alters subcellular localization. J Virol 80 12070 12078