1887

Abstract

Rabies virus (RABV) infection can initiate the host immune defence response and induce an antiviral state characterized by the expression of interferon (IFN)-stimulated genes (ISGs), among which the family of genes of IFN-induced protein with tetratricopeptide repeats (Ifits) are prominent representatives. Herein, we demonstrated that the mRNA and protein levels of Ifit1, Ifit2 and Ifit3 were highly increased in cultured cells and mouse brains after RABV infection. Recombinant RABV expressing Ifit3, designated rRABV-Ifit3, displayed a lower pathogenicity than the parent RABV in C57BL/6 mice after intramuscular administration, and Ifit3-deficient mice exhibited higher susceptibility to RABV infection and higher mortality during RABV infection. Moreover, compared with their individual expressions, co-expression of Ifit2 and Ifit3 could more effectively inhibit RABV replication . These results indicate that murine Ifit3 plays an essential role in restricting the replication and reducing the pathogenicity of RABV. Ifit3 acts synergistically with Ifit2 to inhibit RABV replication, providing further insight into the function and complexity of the Ifit family.

Funding
This study was supported by the:
  • Young Scientists Fund (Award 31702248)
    • Principle Award Recipient: DayongTian
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/content/journal/jgv/10.1099/jgv.0.001619
2021-07-16
2024-04-24
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References

  1. Guo Z, Tao X, Yin C, Han N, Yu J et al. National borders effectively halt the spread of rabies: The current rabies epidemic in China is dislocated from cases in neighboring countries. PLoS Negl Trop Dis 2013; 7:e2039 [View Article] [PubMed]
    [Google Scholar]
  2. Albertini AA, Ruigrok RW, Blondel D. Rabies virus transcription and replication. Adv Virus Res 2011; 79:1–22 [View Article] [PubMed]
    [Google Scholar]
  3. Li J, Faber M, Dietzschold B, Hooper DC. The role of toll-like receptors in the induction of immune responses during rabies virus infection. Adv Virus Res 2011; 79:115–126 [View Article] [PubMed]
    [Google Scholar]
  4. Luo Z, Lv L, Li Y, Sui B, Wu Q et al. Dual role of toll-like receptor 7 in the pathogenesis of Rabies virus in a mouse model. J Virol 2020; 94: [View Article]
    [Google Scholar]
  5. Faul EJ, Wanjalla CN, Suthar MS, Gale M, Wirblich C et al. Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. PLoS Pathog 2010; 6:e1001016 [View Article] [PubMed]
    [Google Scholar]
  6. Rieder M, Conzelmann KK. Interferon in rabies virus infection. Adv Virus Res 2011; 79:91–114 [View Article] [PubMed]
    [Google Scholar]
  7. Grandvaux N, Servant MJ, tenOever B, Sen GC, Balachandran S et al. Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J Virol 2002; 76:5532–5539 [View Article] [PubMed]
    [Google Scholar]
  8. White CL, Kessler PM, Dickerman BK, Ozato K, Sen GC. Interferon regulatory factor 8 (irf8) impairs induction of interferon induced with tetratricopeptide repeat motif (IFIT) gene family members. J Biol Chem 2016; 291:13535–13545 [View Article] [PubMed]
    [Google Scholar]
  9. Daugherty MD, Schaller AM, Geballe AP, Malik HS. Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals. Elife 2016; 5: [View Article] [PubMed]
    [Google Scholar]
  10. Zhou X, Michal JJ, Zhang L, Ding B, Lunney JK et al. Interferon induced IFIT family genes in host antiviral defense. Int J Biol Sci 2013; 9:200–208 [View Article] [PubMed]
    [Google Scholar]
  11. Mears HV, Sweeney TR. Mouse Ifit1b is a cap1-RNA-binding protein that inhibits mouse coronavirus translation and is regulated by complexing with Ifit1c. J Biol Chem 2020; 295:17781–17801 [View Article] [PubMed]
    [Google Scholar]
  12. Fensterl V, White CL, Yamashita M, Sen GC. Novel characteristics of the function and induction of murine p56 family proteins. J Virol 2008; 82:11045–11053 [View Article] [PubMed]
    [Google Scholar]
  13. Fensterl V, Sen GC. The ISG56/IFIT1 gene family. J Interferon Cytokine Res 2011; 31:71–78 [View Article] [PubMed]
    [Google Scholar]
  14. Vladimer GI, Górna MW, Superti-Furga G. Ifits: Emerging roles as key anti-viral proteins. Front Immunol 2014; 5:94 [View Article] [PubMed]
    [Google Scholar]
  15. Diamond MS, Farzan M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 2013; 13:46–57 [View Article] [PubMed]
    [Google Scholar]
  16. Schoggins JW. Recent advances in antiviral interferon-stimulated gene biology. F1000Res 2018; 7:309 [View Article] [PubMed]
    [Google Scholar]
  17. Terenzi F, White C, Pal S, Williams BR, Sen GC. Tissue-specific and inducer-specific differential induction of ISG56 and ISG54 in mice. J Virol 2007; 81:8656–8665 [View Article] [PubMed]
    [Google Scholar]
  18. Wacher C, Müller M, Hofer MJ, Getts DR, Zabaras R et al. Coordinated regulation and widespread cellular expression of interferon-stimulated genes (ISG) ISG-49, ISG-54, and ISG-56 in the central nervous system after infection with distinct viruses. J Virol 2007; 81:860–871 [View Article] [PubMed]
    [Google Scholar]
  19. Diamond MS. IFIT1: A dual sensor and effector molecule that detects non-2’-O methylated viral RNA and inhibits its translation. Cytokine Growth Factor Rev 2014; 25:543–550 [View Article] [PubMed]
    [Google Scholar]
  20. Andrejeva J, Norsted H, Habjan M, Thiel V, Goodbourn S et al. ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis. J Gen Virol 2013; 94:59–68 [View Article] [PubMed]
    [Google Scholar]
  21. Young DF, Andrejeva J, Li X, Inesta-Vaquera F, Dong C et al. Human IFIT1 inhibits mrna translation of rubulaviruses but not other members of the Paramyxoviridae family. J Virol 2016; 90:9446–9456 [View Article] [PubMed]
    [Google Scholar]
  22. Reynaud JM, Kim DY, Atasheva S, Rasalouskaya A, White JP et al. IFIT1 differentially interferes with translation and replication of alphavirus genomes and promotes induction of type I interferon. PLoS Pathog 2015; 11:e1004863 [View Article] [PubMed]
    [Google Scholar]
  23. Mears HV, Emmott E, Chaudhry Y, Hosmillo M, Goodfellow IG et al. Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells. Wellcome Open Res 2019; 4:82 [View Article] [PubMed]
    [Google Scholar]
  24. Kimura T, Katoh H, Kayama H, Saiga H, Okuyama M et al. Ifit1 inhibits Japanese encephalitis virus replication through binding to 5’ capped 2’-O unmethylated RNA. J Virol 2013; 87:9997–10003 [View Article] [PubMed]
    [Google Scholar]
  25. Fensterl V, Wetzel JL, Ramachandran S, Ogino T, Stohlman SA et al. Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis. PLoS Pathog 2012; 8:e1002712 [View Article] [PubMed]
    [Google Scholar]
  26. Fensterl V, Wetzel JL, Sen GC. Interferon-induced protein Ifit2 protects mice from infection of the peripheral nervous system by vesicular stomatitis virus. J Virol 2014; 88:10303–10311 [View Article] [PubMed]
    [Google Scholar]
  27. Cho H, Shrestha B, Sen GC, Diamond MS. A role for Ifit2 in restricting West Nile virus infection in the brain. J Virol 2013; 87:8363–8371 [View Article] [PubMed]
    [Google Scholar]
  28. Wetzel JL, Fensterl V, Sen GC. Sendai virus pathogenesis in mice is prevented by Ifit2 and exacerbated by interferon. J Virol 2014; 88:13593–13601 [View Article] [PubMed]
    [Google Scholar]
  29. Butchi NB, Hinton DR, Stohlman SA, Kapil P, Fensterl V et al. Ifit2 deficiency results in uncontrolled neurotropic coronavirus replication and enhanced Encephalitis via impaired alpha/beta interferon induction in macrophages. J Virol 2014; 88:1051–1064 [View Article] [PubMed]
    [Google Scholar]
  30. Davis BM, Fensterl V, Lawrence TM, Hudacek AW, Sen GC et al. Ifit2 is a restriction factor in rabies virus pathogenicity. J Virol 2017; 91:17 [View Article]
    [Google Scholar]
  31. Tian D, Luo Z, Zhou M, Li M, Yu L et al. Critical role of k1685 and k1829 in the large protein of Rabies virus in viral pathogenicity and immune evasion. J Virol 2016; 90:232–244 [View Article] [PubMed]
    [Google Scholar]
  32. Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991; 108:193–199 [View Article] [PubMed]
    [Google Scholar]
  33. Li Y, Zhao L, Luo Z, Zhang Y, Lv L et al. Interferon-λ attenuates Rabies virus infection by inducing interferon-stimulated genes and alleviating neurological inflammation. Viruses 2020; 12: [View Article]
    [Google Scholar]
  34. Zhao L, Toriumi H, Kuang Y, Chen H, ZF F. The roles of chemokines in rabies virus infection: Overexpression may not always be beneficial. J Virol 2009; 83:11808–11818
    [Google Scholar]
  35. Sui B, Chen D, Liu W, Wu Q, Tian B et al. A novel antiviral lncRNA, EDAL, shields a T309 O-GlcNAcylation site to promote EZH2 lysosomal degradation. Genome Biol 2020; 21:228 [View Article] [PubMed]
    [Google Scholar]
  36. Sen GC, Peters GA. Viral stress-inducible genes. Adv Virus Res 2007; 70:233–263 [View Article] [PubMed]
    [Google Scholar]
  37. Fleith RC, Mears HV, Leong XY, Sanford TJ, Emmott E et al. IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA. Nucleic Acids Res 2018; 46:5269–5285 [View Article] [PubMed]
    [Google Scholar]
  38. Johnson B, VanBlargan LA, Xu W, White JP, Shan C et al. Human IFIT3 modulates IFIT1 RNA binding specificity and protein stability. Immunity 2018; 48:487–499e485 [View Article] [PubMed]
    [Google Scholar]
  39. Kimura T, Flynn CT, Alirezaei M, Sen GC, Whitton JL. Biphasic and cardiomyocyte-specific IFIT activity protects cardiomyocytes from enteroviral infection. PLoS Pathog 2019; 15:e1007674 [View Article] [PubMed]
    [Google Scholar]
  40. Pinto AK, Williams GD, Szretter KJ, White JP, Proença-Módena JL et al. Human and murine IFIT1 proteins do not restrict infection of negative-sense RNA viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families. J Virol 2015; 89:9465–9476 [View Article] [PubMed]
    [Google Scholar]
  41. Abbas YM, Pichlmair A, Górna MW, Superti-Furga G, Nagar B. Structural basis for viral 5’-PPP-RNA recognition by human IFIT proteins. Nature 2013; 494:60–64 [View Article] [PubMed]
    [Google Scholar]
  42. Pichlmair A, Lassnig C, Eberle CA, Górna MW, Baumann CL et al. IFIT1 is an antiviral protein that recognizes 5’-triphosphate RNA. Nat Immunol 2011; 12:624–630 [View Article] [PubMed]
    [Google Scholar]
  43. Abbas YM, Laudenbach BT, Martínez-Montero S, Cencic R, Habjan M et al. Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2’-O methylations. Proc Natl Acad Sci U S A 2017; 114:e2106–e2115 [View Article]
    [Google Scholar]
  44. Yang Z, Liang H, Zhou Q, Li Y, Chen H et al. Crystal structure of ISG54 reveals a novel RNA binding structure and potential functional mechanisms. Cell Res 2012; 22:1328–1338 [View Article] [PubMed]
    [Google Scholar]
  45. Habjan M, Hubel P, Lacerda L, Benda C, Holze C et al. Sequestration by IFIT1 impairs translation of 2’O-unmethylated capped RNA. PLoS Pathog 2013; 9:e1003663 [View Article]
    [Google Scholar]
  46. Daffis S, Szretter KJ, Schriewer J, Li J, Youn S et al. 2’-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 2010; 468:452–456 [View Article] [PubMed]
    [Google Scholar]
  47. Hyde JL, Diamond MS. Innate immune restriction and antagonism of viral RNA lacking 2-o methylation. Virology 2015; 479–480:66–74 [View Article] [PubMed]
    [Google Scholar]
  48. Szretter KJ, Daniels BP, Cho H, Gainey MD, Yokoyama WM et al. 2’-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo. PLoS Pathog 2012; 8:e1002698 [View Article] [PubMed]
    [Google Scholar]
  49. Horwitz JA, Jenni S, Harrison SC, Whelan SPJ. Structure of a rabies virus polymerase complex from electron cryo-microscopy. Proc Natl Acad Sci U S A 2020; 117:2099–2107 [View Article] [PubMed]
    [Google Scholar]
  50. Imaizumi T, Yoshida H, Hayakari R, Xing F, Wang L et al. Interferon-stimulated gene (ISG) 60, as well as ISG56 and ISG54, positively regulates TLR3/IFN-β/STAT1 axis in U373MG human astrocytoma cells. Neurosci Res 2016; 105:35–41 [View Article] [PubMed]
    [Google Scholar]
  51. Li D, Swaminathan S. Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system. PLoS Pathog 2019; 15:e1007609 [View Article] [PubMed]
    [Google Scholar]
  52. Schmeisser H, Mejido J, Balinsky CA, Morrow AN, Clark CR et al. Identification of alpha interferon-induced genes associated with antiviral activity in Daudi cells and characterization of IFIT3 as a novel antiviral gene. J Virol 2010; 84:10671–10680 [View Article] [PubMed]
    [Google Scholar]
  53. Liu XY, Chen W, Wei B, Shan YF, Wang C. IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. J Immunol 2011; 187:2559–2568 [View Article] [PubMed]
    [Google Scholar]
  54. Kumar P, Sweeney TR, Skabkin MA, Skabkina OV, Hellen CU et al. Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5’-terminal regions of cap0-, cap1- and 5’ppp- mRNAs. Nucleic Acids Res 2014; 42:3228–3245 [View Article] [PubMed]
    [Google Scholar]
  55. Pidugu VK, MM W, Yen AH, Pidugu HB, Chang KW et al. IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling. Oncogene 2019; 38:3232–3247 [View Article]
    [Google Scholar]
  56. Mears HV, Sweeney TR. Better together: The role of IFIT protein-protein interactions in the antiviral response. J Gen Virol 2018; 99:1463–1477 [View Article] [PubMed]
    [Google Scholar]
  57. Siegfried A, Berchtold S, Manncke B, Deuschle E, Reber J et al. IFIT2 is an effector protein of type I IFN-mediated amplification of lipopolysaccharide (LPS)-induced TNF-α secretion and LPS-induced endotoxin shock. J Immunol 2013; 191:3913–3921 [View Article] [PubMed]
    [Google Scholar]
  58. Terenzi F, Hui DJ, Merrick WC, Sen GC. Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56. J Biol Chem 2006; 281:34064–34071 [View Article] [PubMed]
    [Google Scholar]
  59. Hui DJ, Bhasker CR, Merrick WC, Sen GC. Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi. J Biol Chem 2003; 278:39477–39482 [View Article] [PubMed]
    [Google Scholar]
  60. Terenzi F, Pal S, Sen GC. Induction and mode of action of the viral stress-inducible murine proteins, p56 and p54. Virology 2005; 340:116–124 [View Article] [PubMed]
    [Google Scholar]
  61. Hui DJ, Terenzi F, Merrick WC, Sen GC. Mouse P56 blocks a distinct function of eukaryotic initiation factor 3 in translation initiation. J Biol Chem 2005; 280:3433–3440 [View Article] [PubMed]
    [Google Scholar]
  62. Stawowczyk M, Van Scoy S, Kumar KP, Reich NC. The interferon stimulated gene 54 promotes apoptosis. J Biol Chem 2011; 286:7257–7266 [View Article] [PubMed]
    [Google Scholar]
  63. Reich NC. A death-promoting role for ISG54/IFIT2. J Interferon Cytokine Res 2013; 33:199–205 [View Article] [PubMed]
    [Google Scholar]
  64. Jiang Z, Su C, Zheng C. Herpes simplex virus 1 tegument protein UL41 counteracts IFIT3 antiviral innate immunity. J Virol 2016; 90:11056–11061 [View Article] [PubMed]
    [Google Scholar]
  65. Liu R, Olano LR, Mirzakhanyan Y, Gershon PD, Moss B. Vaccinia virus ankyrin-repeat/F-box protein targets interferon-induced IFITs for proteasomal degradation. Cell Rep 2019; 29:816–828 [View Article] [PubMed]
    [Google Scholar]
  66. Xu F, Song H, An B, Xiao Q, Cheng G et al. NF-κB-Dependent IFIT3 Induction by HBx Promotes Hepatitis B Virus Replication. Front Microbiol 2019; 10:2382 [View Article] [PubMed]
    [Google Scholar]
  67. Terenzi F, Saikia P, Sen GC. Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1. Embo j 2008; 27:3311–3321 [View Article] [PubMed]
    [Google Scholar]
  68. McDermott JE, Vartanian KB, Mitchell H, Stevens SL, Sanfilippo A et al. Identification and validation of Ifit1 as an important innate immune bottleneck. PLoS One 2012; 7:e36465 [View Article]
    [Google Scholar]
  69. Berchtold S, Manncke B, Klenk J, Geisel J, Autenrieth IB et al. Forced IFIT-2 expression represses LPS induced TNF-alpha expression at posttranscriptional levels. BMC Immunol 2008; 9:75 [View Article] [PubMed]
    [Google Scholar]
  70. John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ et al. IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages. Cell Rep 2018; 25:95–106e106 [View Article] [PubMed]
    [Google Scholar]
  71. Li C, Li C, Xue P, Zhong B, Mao AP et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proc Natl Acad Sci U S A 2009; 106:7945–7950 [View Article] [PubMed]
    [Google Scholar]
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