Melanoma Differentiation-Associated Gene 5 (MDA5) Is Involved in the Innate Immune Response to Infection In Vivo


The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses.


Vyšlo v časopise: Melanoma Differentiation-Associated Gene 5 (MDA5) Is Involved in the Innate Immune Response to Infection In Vivo. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000734
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000734

Souhrn

The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses.


Zdroje

1. KawaiT

AkiraS

2008 Toll-like Receptor and RIG-1-like Receptor Signaling. Annals of the New York Academy of Sciences 1143 1 20

2. KotenkoSV

PestkaS

2000 Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19 2557 2565

3. SchindlerC

DarnellJE

1995 Transcriptional Responses to Polypeptide Ligands: The JAK-STAT Pathway. Annual Review of Biochemistry 64 621 652

4. de VeerMJ

HolkoM

FrevelM

WalkerE

DerS

2001 Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 69 912 920

5. StetsonDB

MedzhitovR

2006 Type I Interferons in Host Defense. Immunity 25 373 381

6. BraunD

CaramalhoI

DemengeotJ

2002 IFN-{alpha}/{beta} enhances BCR-dependent B cell responses. Int Immunol 14 411 419

7. ToughDF

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

8. SaitoT

HiraiR

LooY-M

OwenD

JohnsonCL

2007 Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proceedings of the National Academy of Sciences 104 582 587

9. IwasakiA

MedzhitovR

2004 Toll-like receptor control of the adaptive immune responses. Nat Immunol 5 987 995

10. AlexopoulouL

HoltAC

MedzhitovR

FlavellRA

2001 Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413 732 738

11. DieboldSS

KaishoT

HemmiH

AkiraS

Reis e SousaC

2004 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.[see comment]. Science 303 1529 1531

12. HeilF

HemmiH

HochreinH

AmpenbergerF

KirschningC

2004 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.[see comment]. Science 303 1526 1529

13. BauerS

KirschningCJ

HäckerH

RedeckeV

HausmannS

2001 Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proceedings of the National Academy of Sciences of the United States of America 98 9237 9242

14. AndrejevaJ

ChildsKS

YoungDF

CarlosTS

StockN

2004 The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proceedings of the National Academy of Sciences of the United States of America 101 17264 17269

15. RothenfusserS

GoutagnyN

DiPernaG

GongM

MonksBG

2005 The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. Journal of Immunology 175 5260 5268

16. SumpterRJr

LooYM

FoyE

LiK

YoneyamaM

2005 Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. Journal of Virology 79 2689 2699

17. YoneyamaM

KikuchiM

MatsumotoK

ImaizumiT

MiyagishiM

2005 Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. Journal of Immunology 175 2851 2858

18. YoneyamaM

KikuchiM

NatsukawaT

ShinobuN

ImaizumiT

2004 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.[see comment]. Nature Immunology 5 730 737

19. KomuroA

HorvathCM

2006 RNA and Virus-Independent Inhibition of Antiviral Signaling by RNA Helicase LGP2. Journal of Virology

20. KangDC

GopalkrishnanRV

WuQ

JankowskyE

PyleAM

2002 mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proceedings of the National Academy of Sciences of the United States of America 99 637 642

21. KovacsovicsM

MartinonF

MicheauO

BodmerJL

HofmannK

2002 Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation.[erratum appears in Curr Biol. 2002 Sep 17;12(18):1633.]. Current Biology 12 838 843

22. VenkataramanT

ValdesM

ElsbyR

KakutaS

CaceresG

2007 Loss of DExD/H Box RNA Helicase LGP2 Manifests Disparate Antiviral Responses. J Immunol 178 6444 6455

23. KawaiT

TakahashiK

SatoS

CobanC

KumarH

2005 IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.[see comment]. Nature Immunology 6 981 988

24. MeylanE

CurranJ

HofmannK

MoradpourD

BinderM

2005 Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 1167 1172

25. SethRB

SunL

EaCK

ChenZJ

2005 Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.[see comment]. Cell 122 669 682

26. XuLG

WangYY

HanKJ

LiLY

ZhaiZ

2005 VISA is an adapter protein required for virus-triggered IFN-beta signaling. Molecular Cell 19 727 740

27. HornungV

EllegastJ

KimS

BrzozkaK

JungA

2006 5′-Triphosphate RNA Is the Ligand for RIG-I. Science 314 994 997

28. PichlmairA

SchulzO

TanCP

NaslundTI

LiljestromP

2006 RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5′-Phosphates. Science 314 997 1001

29. KatoH

TakeuchiO

Mikamo-SatohE

HiraiR

KawaiT

2008 Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205 1601 1610

30. SaitoT

GaleMJr

2008 Differential recognition of double-stranded RNA by RIG-I-like receptors in antiviral immunity. J Exp Med 205 1523 1527

31. SaitoT

OwenDM

JiangF

MarcotrigianoJ

GaleMJr

2008 Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454 523 527

32. GitlinL

BarchetW

GilfillanS

CellaM

BeutlerB

2006 Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proceedings of the National Academy of Sciences of the United States of America 103 8459 8464

33. KatoH

TakeuchiO

SatoS

YoneyamaM

YamamotoM

2006 Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441 101 105

34. LooY-M

FornekJ

CrochetN

BajwaG

PerwitasariO

2008 Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity. J Virol 82 335 345

35. McCartneySA

ThackrayLB

GitlinL

GilfillanS

Virgin IvHW

2008 MDA-5 Recognition of a Murine Norovirus. PLoS Pathog 4 e1000108 doi:10.1371/journal.ppat.1000108

36. FredericksenBL

KellerBC

FornekJ

KatzeMG

GaleMJr

2008 Establishment and Maintenance of the Innate Antiviral Response to West Nile Virus Involves both RIG-I and MDA5 Signaling through IPS-1. J Virol 82 609 616

37. CollinsPL

ChanockRM

McIntoshK

1996 Parainfluenza Viruses.

Fields

Fields Virology Philadelphia Lippincott-Raven

38. CollinsPL

ChanockRM

McIntoshK

1996 Respiratory Syncytial Virus. Fields Virology Philadelphia Lippincott-Raven

39. WalterMJ

KajiwaraN

KaranjaP

CastroM

HoltzmanMJ

2001 Interleukin 12 p40 Production by Barrier Epithelial Cells during Airway Inflammation. J Exp Med 193 339 352

40. HausmannS

MarqJ-B

TapparelC

KolakofskyD

GarcinD

2008 RIG-I and dsRNA-Induced IFNÎ2 Activation. PLoS ONE 3 e3965 doi:10.1371/journal.pone.0003965

41. StrahleL

MarqJ-B

BriniA

HausmannS

KolakofskyD

2007 Activation of the Beta Interferon Promoter by Unnatural Sendai Virus Infection Requires RIG-I and Is Inhibited by Viral C Proteins. J Virol 81 12227 12237

42. GarcinD

LatorreP

KolakofskyD

1999 Sendai Virus C Proteins Counteract the Interferon-Mediated Induction of an Antiviral State. J Virol 73 6559 6565

43. GotohB

TakeuchiK

KomatsuT

YokooJ

KimuraY

1999 Knockout of the Sendai virus C gene eliminates the viral ability to prevent the interferon-[alpha]/[beta]-mediated responses. FEBS Letters 459 205 210

44. ChildsK

StockN

RossC

AndrejevaJ

HiltonL

2007 mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359 190 200

45. YountJS

GitlinL

MoranTM

LopezCB

2008 MDA5 Participates in the Detection of Paramyxovirus Infection and Is Essential for the Early Activation of Dendritic Cells in Response to Sendai Virus Defective Interfering Particles. J Immunol 180 4910 4918

46. ParkerJC

WhitemanMD

RichterCB

1978 Susceptibility of inbred and outbred mouse strains to Sendai virus and prevalence of infection in laboratory rodents. Infect Immun 19 123 130

47. ItohT

IwaiH

UedaK

1991 Comparative lung pathology of inbred strain of mice resistant and susceptible to Sendai virus infection. Journal of Veterinary Medical Science 53 275 279

48. MoXY

SarawarSR

DohertyPC

1995 Induction of cytokines in mice with parainfluenza pneumonia. J Virol 69 1288 1291

49. BlandfordG

HeathRB

1972 Studies on the immune response and pathogenesis of Sendai virus infection of mice. I. The fate of viral antigens. Immunology 22 637 649

50. DegréM

MidtvedtT

1971 Respiratory infection with parainfluenza 1, Sendai virus in gnotobiotic and conventional mice. Acta pathologica et microbiologica Scandinavica Section B: Microbiology and immunology 79 123 124

51. BrownsteinDGSA

JohnsonEA

1981 Sendai virus infection in genetically resistant and susceptible mice. The American journal of pathology 105 156 163

52. TakeuchiK

KomatsuT

YokooJ

KatoA

ShiodaT

2001 Sendai virus C protein physically associates with Stat1. Genes to Cells 6 545 557

53. ShornickLP

WellsAG

ZhangY

PatelAC

HuangG

2008 Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection. J Immunol 180 3319 3328

54. LopezCB

MoltedoB

AlexopoulouL

BonifazL

FlavellRA

2004 TLR-Independent Induction of Dendritic Cell Maturation and Adaptive Immunity by Negative-Strand RNA Viruses. J Immunol 173 6882 6889

55. MelchjorsenJ

JensenSB

MalmgaardL

RasmussenSB

WeberF

2005 Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. Journal of Virology 79 12944 12951

56. KatoA

KiyotaniK

SakaiY

YoshidaT

NagaiY

1997 The paramyxovirus, Sendai virus, V protein encodes a luxury function required for viral pathogenesis. EMBO (European Molecular Biology Organization) Journal 16 578 587

57. LeiY

MooreCB

LiesmanRM

O'ConnorBP

BergstralhDT

2009 MAVS-Mediated Apoptosis and Its Inhibition by Viral Proteins. PLoS ONE 4 e5466 doi:10.1371/journal.pone.0005466

58. PetersK

ChattopadhyayS

SenGC

2008 IRF-3 Activation by Sendai Virus Infection Is Required for Cellular Apoptosis and Avoidance of Persistence. J Virol 82 3500 3508

59. KiyotaniK

SakaguchiT

KatoA

NagaiY

YoshidaT

2007 Paramyxovirus Sendai virus V protein counteracts innate virus clearance through IRF-3 activation, but not via interferon, in mice. Virology 359 82 91

60. ParisienJ-P

BammingD

KomuroA

RamachandranA

RodriguezJJ

2009 A Shared Interface Mediates Paramyxovirus Interference with Antiviral RNA Helicases MDA5 and LGP2. J Virol JVI.00153 00109

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