Deficient IFN Signaling by Myeloid Cells Leads to MAVS-Dependent Virus-Induced Sepsis

English version České info

Although it is well established that the interferon (IFN) signaling pathway restricts infection by many viruses, the key cell types in vivo that contribute to this process remain poorly characterized. To address this question in the context of West Nile virus (WNV) pathogenesis, we infected mice that specifically delete the type I IFN receptor gene (Ifnar) in subsets of myeloid cells, including dendritic cells and macrophages. Remarkably, mice lacking Ifnar expression only in myeloid cell subsets rapidly developed a sepsis-like syndrome that was characterized by enhanced WNV infection and visceral organ injury and caused by massive proinflammatory cytokine production and complement activation. By using additional gene targeted deletion mice, we show that WNV infection triggered signaling through the RIG-I like receptor adaptor protein MAVS to cause complement activation, sepsis, and tissue damage. Indeed, liver damage was minimized in animals lacking specific complement components, or treated with neutralizing anti-complement or anti-TNF-α antibodies. Our results establish how type I IFN signaling in dendritic cells and macrophages restricts infection, controls inflammatory cascades, and prevents pathogenesis in vivo.

Vyšlo v časopise: Deficient IFN Signaling by Myeloid Cells Leads to MAVS-Dependent Virus-Induced Sepsis. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004086
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004086

Souhrn

Zdroje

1. IsaacsA, LindenmannJ (1957) Virus Interference. I. The Interferon. Proceedings of the Royal Society of London Series B - Biological Sciences 147: 258–267.

2. TrinchieriG (2010) Type I interferon: friend or foe? J Exp Med 207: 2053–2063.

3. ChoH, ProllSC, SzretterKJ, KatzeMG, GaleMJr, et al. (2013) Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat Med 19: 458–464.

4. SchogginsJW, WilsonSJ, PanisM, MurphyMY, JonesCT, et al. (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472: 481–485.

5. CorbiAL, Lopez-RodriguezC (1997) CD11c integrin gene promoter activity during myeloid differentiation. Leuk Lymphoma 25: 415–425.

6. MetlayJP, Witmer-PackMD, AggerR, CrowleyMT, LawlessD, et al. (1990) The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med 171: 1753–1771.

7. VinayDS, KwonBS (2010) CD11c+CD8+ T cells: Two-faced adaptive immune regulators. Cellular Immunology 264: 18–22.

8. SutharMS, DiamondMS, GaleMJr (2013) West Nile virus infection and immunity. Nat Rev Microbiol 11: 115–128.

9. ByrneSN, HallidayGM, JohnstonLJ, KingNJC (2001) Interleukin-1[bgr] But Not Tumor Necrosis Factor is Involved in West Nile Virus-Induced Langerhans Cell Migration from the Skin in C57BL//6 Mice. 117: 702–709.

10. LimPY, BehrMJ, ChadwickCM, ShiPY, BernardKA (2011) Keratinocytes are cell targets of West Nile virus in vivo. J Virol 85: 5197–5201.

11. JohnstonLJ, HallidayGM, KingNJ (2000) Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus. J Invest Dermatol 114: 560–568.

12. SamuelMA, DiamondMS (2005) Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 79: 13350–13361.

13. SutharMS, BrassilMM, BlahnikG, McMillanA, RamosHJ, et al. (2013) A Systems Biology Approach Reveals that Tissue Tropism to West Nile Virus Is Regulated by Antiviral Genes and Innate Immune Cellular Processes. PLoS Pathog 9: e1003168.

14. SutharMS, MaDY, ThomasS, LundJM, ZhangN, et al. (2010) IPS-1 Is Essential for the Control of West Nile Virus Infection and Immunity. PLoS Pathog 6: e1000757.

15. DurrantDM, RobinetteML, KleinRS (2013) IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis. J Exp Med 210: 503–516.

16. KumarM, RoeK, OrilloB, MuruveDA, NerurkarVR, et al. (2013) Inflammasome Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD (ASC) Is Critical for the Immune Response and Survival in West Nile Virus Encephalitis. J Virol 87: 3655–3667.

17. RamosHJ, LanteriMC, BlahnikG, NegashA, SutharMS, et al. (2012) IL-1beta signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog 8: e1003039.

18. PintoAK, DaffisS, BrienJD, GaineyMD, YokoyamaWM, et al. (2011) A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection. PLoS Pathog 7: e1002407.

19. PrinzM, SchmidtH, MildnerA, KnobelochKP, HanischUK, et al. (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28: 675–686.

20. Cervantes-BarraganL, KalinkeU, ZustR, KonigM, ReizisB, et al. (2009) Type I IFN-mediated protection of macrophages and dendritic cells secures control of murine coronavirus infection. J Immunol 182: 1099–1106.

21. KernbauerE, MaierV, StoiberD, StroblB, SchneckenleithnerC, et al. (2012) Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. PLoS Pathog 8: e1002763.

22. ThackrayLB, DuanE, LazearHM, KambalA, SchreiberRD, et al. (2012) Critical Role for Interferon Regulatory Factor 3 (IRF-3) and IRF-7 in Type I Interferon-Mediated Control of Murine Norovirus Replication. J Virol 86: 13515–13523.

23. SamuelMA, DiamondMS (2006) Pathogenesis of West Nile virus infection: A balance between virulence, innate and adaptive immunity, and viral evasion. J Virol 80: 9349–9360.

24. ShresthaB, GottliebD, DiamondMS (2003) Infection and injury of neurons by West Nile encephalitis virus. J Virol 77: 13203–13213.

25. XiaoSY, GuzmanH, ZhangH, Travassos da RosaAP, TeshRB (2001) West Nile virus infection in the golden hamster (Mesocricetus auratus): a model for West Nile encephalitis. Emerg Infect Dis 7: 714–721.

26. DiamondMS, KinderM, MatsushitaH, MashayekhiM, DunnGP, et al. (2011) Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 208: 1989–2003.

27. SourisseauM, SchilteC, CasartelliN, TrouilletC, Guivel-BenhassineF, et al. (2007) Characterization of Reemerging Chikungunya Virus. PLoS Pathog 3: e89.

28. CoudercT, ChrétienF, SchilteC, DissonO, BrigitteM, et al. (2008) A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease. PLoS Pathog 4: e29.

29. MillerSI, WallaceRJJr, MusherDM, SeptimusEJ, KohlS, et al. (1980) Hypoglycemia as a manifestation of sepsis. Am J Med 68: 649–654.

30. SubramanianN, NatarajanK, ClatworthyMR, WangZ, GermainRN (2013) The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation. Cell 153: 348–361.

31. DaffisS, SamuelMA, KellerBC, GaleMJr, DiamondMS (2007) Cell-specific IRF-3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms. PLoS Pathog 3: e106.

32. DaffisS, SamuelMA, SutharMS, KellerBC, GaleMJr, et al. (2008) Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection. J Virol 82: 8465–8475.

33. DaffisS, SutharMS, GaleMJr, DiamondMS (2009) Measure and countermeasure: type I IFN (IFN-alpha/beta) antiviral response against West Nile virus. J Innate Immun 1: 435–445.

34. DaffisS, SutharMS, SzretterKJ, GaleMJr, DiamondMS (2009) Induction of IFN-beta and the innate antiviral response in myeloid cells occurs through an IPS-1-dependent signal that does not require IRF-3 and IRF-7. PLoS Pathog 5: e1000607.

35. LazearHM, LancasterA, WilkinsC, SutharMS, HuangA, et al. (2013) IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling. PLoS Pathog 9: e1003118.

36. LazearHM, PintoAK, VogtMR, GaleMJr, DiamondMS (2011) Beta interferon controls West Nile virus infection and pathogenesis in mice. J Virol 85: 7186–7194.

37. PalP, DowdKA, BrienJD, EdelingMA, GorlatovS, et al. (2013) Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus. PLoS Pathog 9: e1003312.

38. GrandvauxN, ServantMJ, tenOeverB, SenGC, BalachandranS, et al. (2002) Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J Virol 76: 5532–5539.

39. DiamondMS, FarzanM (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13: 46–57.

40. ShresthaB, ZhangB, PurthaWE, KleinRS, DiamondMS (2008) Tumor necrosis factor alpha protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system. J Virol 82: 8956–8964.

41. YamanakaA, HendriantoE, MulyatnoKC, SusilowatiH, GintingAP, et al. (2013) Correlation between complement component levels and disease severity in dengue patients in Indonesia. Jpn J Infect Dis 66: 366–374.

42. BokischVA, TopFHJr, RussellPK, DixonFJ, Muller-EberhardHJ (1973) The potential pathogenic role of complement in dengue hemorrhagic shock syndrome. N Engl J Med 289: 996–1000.

43. BokischVA, Muller-EberhardHJ, DixonFJ (1973) The role of complement in hemorrhagic shock syndrome (dengue). Trans Assoc Am Physicians 86: 102–110.

44. GoringK, HuangY, MowatC, LegerC, LimTH, et al. (2009) Mechanisms of human complement factor B induction in sepsis and inhibition by activated protein C. Am J Physiol Cell Physiol 296: C1140–1150.

45. PurthaWE, ChachuKA, VirginHWt, DiamondMS (2008) Early B-cell activation after West Nile virus infection requires alpha/beta interferon but not antigen receptor signaling. J Virol 82: 10964–10974.

46. TangBL (2012) The cell biology of Chikungunya virus infection. Cell Microbiol 14: 1354–1363.

47. TisoncikJR, KorthMJ, SimmonsCP, FarrarJ, MartinTR, et al. (2012) Into the Eye of the Cytokine Storm. Microbiology and Molecular Biology Reviews 76: 16–32.

48. WangH, MaS (2008) The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. The American Journal of Emergency Medicine 26: 711–715.

49. DongT, MoranE, Vinh ChauN, SimmonsC, LuhnK, et al. (2007) High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection. PLoS One 2: e1192.

50. HoberD, DelannoyAS, BenyoucefS, De GrooteD, WattreP (1996) High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol Immunol 40: 569–573.

51. ShrestaS, ShararKL, PrigozhinDM, BeattyPR, HarrisE (2006) Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 80: 10208–10217.

52. DavisBK, WenH, TingJP-Y (2011) The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases. Annu Rev Immunol 29: 707–735.

53. MartinonF, BurnsK, TschoppJ (2002) The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-β. Molecular Cell 10: 417–426.

54. ArjonaA, LedizetM, AnthonyK, BonaféN, ModisY, et al. (2007) West Nile Virus Envelope Protein Inhibits dsRNA-Induced Innate Immune Responses. The Journal of Immunology 179: 8403–8409.

55. KongK-F, DelrouxK, WangX, QianF, ArjonaA, et al. (2008) Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly. J Virol 82: 7613–7623.

56. TownT, BaiF, WangT, KaplanAT, QianF, et al. (2009) Toll-like Receptor 7 Mitigates Lethal West Nile Encephalitis via Interleukin 23-Dependent Immune Cell Infiltration and Homing. Immunity 30: 242–253.

57. WangP, ArjonaA, ZhangY, SultanaH, DaiJ, et al. (2010) Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I. Nat Immunol 11: 912–919.

58. HenryT, BrotckeA, WeissDS, ThompsonLJ, MonackDM (2007) Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J Exp Med 204: 987–994.

59. 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.

60. KellerBC, FredericksenBL, SamuelMA, MockRE, MasonPW, et al. (2006) Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence. J Virol 80: 9424–9434.

61. FredericksenBL, GaleMJr (2006) West Nile virus evades activation of interferon regulatory factor 3 through RIG-I-dependent and -independent pathways without antagonizing host defense signaling. J Virol 80: 2913–2923.

62. FredericksenBL, SmithM, KatzeMG, ShiPY, GaleMJr (2004) The host response to West Nile Virus infection limits viral spread through the activation of the interferon regulatory factor 3 pathway. J Virol 78: 7737–7747.

63. MatsukiT, BeachJM, KlindtRL, DulingBR (1993) Modification of vascular reactivity by alteration of intimal permeability: effect of TNF-alpha. Am J Physiol 264: H1847–1853.

64. SobeyCG, DustingGJ, StewartAG (1992) Tumour necrosis factor alpha augments the release of an endothelium-dependent vasoconstrictor from human polymorphonuclear leukocytes. J Cardiovasc Pharmacol 20: 813–819.

65. WalshLJ, TrinchieriG, WaldorfHA, WhitakerD, MurphyGF (1991) Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci U S A 88: 4220–4224.

66. MehlhopE, DiamondMS (2006) Protective immune responses against West Nile virus are primed by distinct complement activation pathways. J Exp Med 203: 1371–1381.

67. SamuelMA, DiamondMS (2005) Type I IFN protects against lethal West Nile Virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 79: 13350–13361.

68. RamachandranA, ParisienJP, HorvathCM (2008) STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition. J Virol 82: 8330–8338.

69. AshourJ, Laurent-RolleM, ShiPY, Garcia-SastreA (2009) NS5 of dengue virus mediates STAT2 binding and degradation. J Virol 83: 5408–5418.

70. ValmasC, GroschMN, SchumannM, OlejnikJ, MartinezO, et al. (2010) Marburg virus evades interferon responses by a mechanism distinct from ebola virus. PLoS Pathog 6: e1000721.

71. SimmonsJD, WollishAC, HeiseMT (2010) A determinant of Sindbis virus neurovirulence enables efficient disruption of Jak/STAT signaling. J Virol 84: 11429–11439.

72. Huber-LangM, SarmaVJ, LuKT, McGuireSR, PadgaonkarVA, et al. (2001) Role of C5a in multiorgan failure during sepsis. J Immunol 166: 1193–1199.

73. CzermakBJ, SarmaV, PiersonCL, WarnerRL, Huber-LangM, et al. (1999) Protective effects of C5a blockade in sepsis. Nat Med 5: 788–792.

74. ZouL, FengY, LiY, ZhangM, ChenC, et al. (2013) Complement Factor B Is the Downstream Effector of TLRs and Plays an Important Role in a Mouse Model of Severe Sepsis. J Immunol 191: 5625–5635.

75. DiamondMS (2009) Mechanisms of Evasion of the Type I Interferon Antiviral Response by Flaviviruses. J Interferon Cytokine Res 29: 521–530.

76. Le BonA, MontoyaM, EdwardsMJ, ThompsonC, BurkeSA, et al. (2006) A role for the transcription factor RelB in IFN-alpha production and in IFN-alpha-stimulated cross-priming. Eur J Immunol 36: 2085–2093.

77. KildsgaardJ, HollmannTJ, MatthewsKW, BianK, MuradF, et al. (2000) Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J Immunol 165: 5406–5409.

78. MehlhopE, DiamondMS (2006) Protective immune responses against West Nile virus are primed by distinct complement activation pathways. J Exp Med 203: 1371–1381.

79. EbelGD, CarricaburuJ, YoungD, BernardKA, KramerLD (2004) Genetic and phenotypic variation of West Nile virus in New York, 2000–2003. Am J Trop Med Hyg 71: 493–500.

80. TsetsarkinK, HiggsS, McGeeCE, De LamballerieX, CharrelRN, et al. (2006) Infectious clones of Chikungunya virus (La Reunion isolate) for vector competence studies. Vector Borne Zoonotic Dis 6: 325–337.

81. SamuelMA, WhitbyK, KellerBC, MarriA, BarchetW, et al. (2006) PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons. J Virol 80: 7009–7019.

82. OliphantT, EngleM, NybakkenGE, DoaneC, JohnsonS, et al. (2005) Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med 11: 522–530.

83. ShanakaWW, RodrigoI, AlcenaDC, RoseRC, JinX, et al. (2009) An Automated Dengue Virus Microneutralization Plaque Assay Performed in Human Fcγ Receptor-expressing CV-1 Cells. Am J Trop Med Hyg 80: 61–65.

84. OliphantT, NybakkenGE, EngleM, XuQ, NelsonCA, et al. (2006) Antibody Recognition and Neutralization Determinants on Domains I and II of West Nile Virus Envelope Protein. J Virol 80: 12149–12159.

85. SzretterKJ, DaffisS, PatelJ, SutharMS, KleinRS, et al. (2010) The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system. J Virol 84: 12125–12138.

86. MehlhopE, FuchsA, EngleM, DiamondMS (2009) Complement modulates pathogenesis and antibody-dependent neutralization of West Nile virus infection through a C5-independent mechanism. Virology 393: 11–15.

87. SheehanKC, LaiKS, DunnGP, BruceAT, DiamondMS, et al. (2006) Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. J Interferon Cytokine Res 26: 804–819.

88. CatonML, Smith-RaskaMR, ReizisB (2007) Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J Exp Med 204: 1653–1664.

89. ClausenBE, BurkhardtC, ReithW, RenkawitzR, ForsterI (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8: 265–277.