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Home / Equine Research Bank / Virology / Role of interferon and interferon regulatory factors in earl...
Virology1999; 257(1); 106-118; doi: 10.1006/viro.1999.9662

Role of interferon and interferon regulatory factors in early protection against Venezuelan equine encephalitis virus infection.

Abstract: To investigate the role of type I interferon (IFN) and its regulatory transacting proteins, interferon regulatory factors (IRF-1 and IRF-2), in early protection against infection with virulent Venezuelan equine encephalitis virus (VEE), we utilized mice with targeted mutations in the IFN-alpha/beta receptor, IRF-1, or IRF-2 genes. IFN-alpha/beta-receptor knockout mice are highly susceptible to peripheral infection with virulent or attenuated VEE, resulting in their death within 24 and 48 h, respectively. Treatment of normal macrophages with anti-IFN-alpha/beta antibody prior to and during infection with molecularly cloned virulent VEE resulted in increased VEE replication. However, treatment with high doses of IFN or IFN-inducing agents failed to alter percentage mortality or average survival times in mice challenged with a low dose of virulent VEE. In IRF-1 and IRF-2 knockout mice (IRF-1(-/-) and IRF-2(-/-)), the 100% protection against virulent VEE that is conferred by attenuated VEE within 24 h in control C57BL/6 mice was completely absent in IRF-2(-/-) mice, whereas 50% of IRF-1(-/-) mice were protected. IRF-2(-/-) mice were deficient in clearing VEE virus from the spleen and the brain compared to the heterozygous IRF-2(+/-) knockout or C57BL/6 (+/+) mice. Furthermore, a distinct pattern of histopathological changes was observed in brains of IRF-2(-/-) mice after VEE exposure. Taken together, these findings imply that the altered immune response in IRF-1 and IRF-2 knockout mice results in altered virus dissemination, altered virus clearance, and altered virus-induced pathology. Thus, type I interferon, as well as IRF-1 and IRF-2, appears to play an important and necessary role in the pathogenesis of, and protection against, VEE infection.
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Publication Date: 1999-04-20 PubMed ID: 10208925DOI: 10.1006/viro.1999.9662Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article investigates the role of type I interferon and interferon regulatory factors in early protection against infection with the Venezuelan equine encephalitis virus (VEE) using gene-targeted mice as subjects.

Methodology and Experimental Approach

  • The researchers used mice with targeted gene mutations of the type I interferon (IFN) and interferon regulatory factors (IRF-1 and IRF-2) to assess their role in early protection against VEE infection.
  • They utilized knockout mice models where specific genes (IFN-alpha/beta receptor, IRF-1, or IRF-2) were deactivated to examine their susceptibility to VEE.
  • Experiments were conducted by treating normal macrophages with anti-IFN-alpha/beta antibody prior to and during infection with VEE to note changes in virus replication.
  • Other procedures involved using high doses of IFN or IFN-inducing agents and assessing how these influenced mortality rates and survival times when mice were exposed to VEE.

Findings and Interpretation

  • IFN-alpha/beta-receptor knockout mice were found to be highly susceptible to VEE, with death occurring within 24 to 48 hours of infection.
  • In normal macrophages, treatment with anti-IFN-alpha/beta antibodies led to increased VEE replication. However, high doses of IFN or IFN-inducing agents had no noticeable effect on mortality rates or survival times in infected mice.
  • IRF knockout mice showed different degrees of protection against VEE. Mice without IRF-2 showed no protection, while half of the mice without IRF-1 were protected.
  • Further, IRF-2(-/-) mice were found deficient in clearing VEE virus from vital organs like the spleen and the brain, leading to discernable changes in the histopathology of their brains post VEE exposure.

Conclusion

  • The research highlights that an altered immune response in mice without IRF-1 and IRF-2 resulted in an altered virus dissemination, clearance, and virus-induced pathology.
  • Valuable insight drawn from this research indicates that type I interferon, along with IRF-1 and IRF-2, plays a crucial role in VEE pathogenesis and potentially protective mechanisms against VEE infection.

Cite This Article

APA
Grieder FB, Vogel SN. (1999). Role of interferon and interferon regulatory factors in early protection against Venezuelan equine encephalitis virus infection. Virology, 257(1), 106-118. https://doi.org/10.1006/viro.1999.9662

Publication

Virology
ISSN: 0042-6822
NlmUniqueID: 0110674
Country: United States
Language: English
Volume: 257
Issue: 1
Pages: 106-118

Researcher Affiliations

Grieder, F B
  • Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814, USA. fgrieder@mxb.usuhs.mil
Vogel, S N

    MeSH Terms

    • Animals
    • DNA-Binding Proteins / genetics
    • DNA-Binding Proteins / physiology
    • Encephalitis Virus, Venezuelan Equine / pathogenicity
    • Encephalomyelitis, Venezuelan Equine / prevention & control
    • Gene Targeting
    • Interferon Regulatory Factor-1
    • Interferon Regulatory Factor-2
    • Interferon Type I / genetics
    • Interferon Type I / physiology
    • Interferon-gamma / genetics
    • Interferon-gamma / physiology
    • Interferons / genetics
    • Interferons / physiology
    • Macrophages, Peritoneal / virology
    • Mice
    • Phosphoproteins / genetics
    • Phosphoproteins / physiology
    • Repressor Proteins / genetics
    • Repressor Proteins / physiology
    • Transcription Factors / genetics
    • Transcription Factors / physiology

    Grant Funding

    • AI-18797 / NIAID NIH HHS
    • R073-DA / NIDA NIH HHS

    Citations

    This article has been cited 47 times.
    1. Kafai NM, Diamond MS, Fox JM. Distinct Cellular Tropism and Immune Responses to Alphavirus Infection.. Annu Rev Immunol 2022 Apr 26;40:615-649.
      doi: 10.1146/annurev-immunol-101220-014952pubmed: 35134315google scholar: lookup
    2. Liu X, Mutso M, Cherkashchenko L, Zusinaite E, Herrero LJ, Doggett SL, Haniotis J, Merits A, Herring BL, Taylor A, Mahalingam S. Identification of Natural Molecular Determinants of Ross River Virus Type I Interferon Modulation.. J Virol 2020 Mar 31;94(8).
      doi: 10.1128/JVI.01788-19pubmed: 31996431google scholar: lookup
    3. Bhalla N, Gardner CL, Downs SN, Dunn M, Sun C, Klimstra WB. Macromolecular Synthesis Shutoff Resistance by Myeloid Cells Is Critical to IRF7-Dependent Systemic Interferon Alpha/Beta Induction after Alphavirus Infection.. J Virol 2019 Dec 15;93(24).
      doi: 10.1128/JVI.00872-19pubmed: 31578290google scholar: lookup
    4. Sharma A, Knollmann-Ritschel B. Current Understanding of the Molecular Basis of Venezuelan Equine Encephalitis Virus Pathogenesis and Vaccine Development.. Viruses 2019 Feb 18;11(2).
      doi: 10.3390/v11020164pubmed: 30781656google scholar: lookup
    5. Kim YG, Baltabekova AZ, Zhiyenbay EE, Aksambayeva AS, Shagyrova ZS, Khannanov R, Ramanculov EM, Shustov AV. Recombinant Vaccinia virus-coded interferon inhibitor B18R: Expression, refolding and a use in a mammalian expression system with a RNA-vector.. PLoS One 2017;12(12):e0189308.
      doi: 10.1371/journal.pone.0189308pubmed: 29216299google scholar: lookup
    6. Carpentier KS, Morrison TE. Innate immune control of alphavirus infection.. Curr Opin Virol 2018 Feb;28:53-60.
      doi: 10.1016/j.coviro.2017.11.006pubmed: 29175515google scholar: lookup
    7. Nair S, Poddar S, Shimak RM, Diamond MS. Interferon Regulatory Factor 1 Protects against Chikungunya Virus-Induced Immunopathology by Restricting Infection in Muscle Cells.. J Virol 2017 Nov 15;91(22).
      doi: 10.1128/JVI.01419-17pubmed: 28835505google scholar: lookup
    8. Lumb JH, Li Q, Popov LM, Ding S, Keith MT, Merrill BD, Greenberg HB, Li JB, Carette JE. DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes.. Cell Rep 2017 Jul 25;20(4):819-831.
      doi: 10.1016/j.celrep.2017.06.085pubmed: 28746868google scholar: lookup
    9. Panda D, Fernandez DJ, Lal M, Buehler E, Moss B. Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants.. Proc Natl Acad Sci U S A 2017 Apr 4;114(14):3720-3725.
      doi: 10.1073/pnas.1700678114pubmed: 28320935google scholar: lookup
    10. Li MM, Bozzacco L, Hoffmann HH, Breton G, Loschko J, Xiao JW, Monette S, Rice CM, MacDonald MR. Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.. J Exp Med 2016 Dec 12;213(13):2931-2947.
      doi: 10.1084/jem.20160303pubmed: 27899441google scholar: lookup
    11. Baxter VK, Griffin DE. Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis.. J Gen Virol 2016 Nov;97(11):2908-2925.
      doi: 10.1099/jgv.0.000613pubmed: 27667782google scholar: lookup
    12. Salimi H, Cain MD, Klein RS. Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis.. Neurotherapeutics 2016 Jul;13(3):514-34.
      doi: 10.1007/s13311-016-0443-5pubmed: 27220616google scholar: lookup
    13. Nenasheva VV, Kovaleva GV, Uryvaev LV, Ionova KS, Dedova AV, Vorkunova GK, Chernyshenko SV, Khaidarova NV, Tarantul VZ. Enhanced expression of trim14 gene suppressed Sindbis virus reproduction and modulated the transcription of a large number of genes of innate immunity.. Immunol Res 2015 Jul;62(3):255-62.
      doi: 10.1007/s12026-015-8653-1pubmed: 25948474google scholar: lookup
    14. Fassbinder-Orth CA, Barak VA, Rainwater EL, Altrichter AM. Buggy Creek virus (Togaviridae: Alphavirus) upregulates expression of pattern recognition receptors and interferons in House Sparrows (Passer domesticus).. Vector Borne Zoonotic Dis 2014 Jun;14(6):439-46.
      doi: 10.1089/vbz.2013.1531pubmed: 24866749google scholar: lookup
    15. Kaur P, Chu JJ. Chikungunya virus: an update on antiviral development and challenges.. Drug Discov Today 2013 Oct;18(19-20):969-83.
      doi: 10.1016/j.drudis.2013.05.002pubmed: 23684571google scholar: lookup
    16. Erwin-Cohen R, Porter A, Pittman P, Rossi C, Dasilva L. Host responses to live-attenuated Venezuelan equine encephalitis virus (TC-83): comparison of naïve, vaccine responder and nonresponder to TC-83 challenge in human peripheral blood mononuclear cells.. Hum Vaccin Immunother 2012 Aug;8(8):1053-65.
      doi: 10.4161/hv.20300pubmed: 22617845google scholar: lookup
    17. Karki S, Li MM, Schoggins JW, Tian S, Rice CM, MacDonald MR. Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity.. PLoS One 2012;7(5):e37398.
      doi: 10.1371/journal.pone.0037398pubmed: 22615998google scholar: lookup
    18. Esen N, Blakely PK, Rainey-Barger EK, Irani DN. Complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice.. ASN Neuro 2012 May 3;4(4):207-21.
      doi: 10.1042/AN20120016pubmed: 22471445google scholar: lookup
    19. Ruotsalainen J, Martikainen M, Niittykoski M, Huhtala T, Aaltonen T, Heikkilä J, Bell J, Vähä-Koskela M, Hinkkanen A. Interferon-β sensitivity of tumor cells correlates with poor response to VA7 virotherapy in mouse glioma models.. Mol Ther 2012 Aug;20(8):1529-39.
      doi: 10.1038/mt.2012.53pubmed: 22434140google scholar: lookup
    20. Mandal P, Krueger BE, Oldenburg D, Andry KA, Beard RS, White DW, Barton ES. A gammaherpesvirus cooperates with interferon-alpha/beta-induced IRF2 to halt viral replication, control reactivation, and minimize host lethality.. PLoS Pathog 2011 Nov;7(11):e1002371.
      doi: 10.1371/journal.ppat.1002371pubmed: 22114555google scholar: lookup
    21. Dionne KR, Galvin JM, Schittone SA, Clarke P, Tyler KL. Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection.. J Neurovirol 2011 Aug;17(4):314-26.
      doi: 10.1007/s13365-011-0038-1pubmed: 21671121google scholar: lookup
    22. Xu C, Guo TC, Mutoloki S, Haugland Ø, Marjara IS, Evensen Ø. Alpha interferon and not gamma interferon inhibits salmonid alphavirus subtype 3 replication in vitro.. J Virol 2010 Sep;84(17):8903-12.
      doi: 10.1128/JVI.00851-10pubmed: 20573808google scholar: lookup
    23. Konopka JL, Thompson JM, Whitmore AC, Webb DL, Johnston RE. Acute infection with venezuelan equine encephalitis virus replicon particles catalyzes a systemic antiviral state and protects from lethal virus challenge.. J Virol 2009 Dec;83(23):12432-42.
      doi: 10.1128/JVI.00564-09pubmed: 19793821google scholar: lookup
    24. Simmons JD, White LJ, Morrison TE, Montgomery SA, Whitmore AC, Johnston RE, Heise MT. Venezuelan equine encephalitis virus disrupts STAT1 signaling by distinct mechanisms independent of host shutoff.. J Virol 2009 Oct;83(20):10571-81.
      doi: 10.1128/JVI.01041-09pubmed: 19656875google scholar: lookup
    25. Bisson SA, Page AL, Ganem D. A Kaposi's sarcoma-associated herpesvirus protein that forms inhibitory complexes with type I interferon receptor subunits, Jak and STAT proteins, and blocks interferon-mediated signal transduction.. J Virol 2009 May;83(10):5056-66.
      doi: 10.1128/JVI.02516-08pubmed: 19279093google scholar: lookup
    26. Barry G, Breakwell L, Fragkoudis R, Attarzadeh-Yazdi G, Rodriguez-Andres J, Kohl A, Fazakerley JK. PKR acts early in infection to suppress Semliki Forest virus production and strongly enhances the type I interferon response.. J Gen Virol 2009 Jun;90(Pt 6):1382-1391.
      doi: 10.1099/vir.0.007336-0pubmed: 19264662google scholar: lookup
    27. Gardner CL, Burke CW, Tesfay MZ, Glass PJ, Klimstra WB, Ryman KD. Eastern and Venezuelan equine encephalitis viruses differ in their ability to infect dendritic cells and macrophages: impact of altered cell tropism on pathogenesis.. J Virol 2008 Nov;82(21):10634-46.
      doi: 10.1128/JVI.01323-08pubmed: 18768986google scholar: lookup
    28. Sharma A, Bhattacharya B, Puri RK, Maheshwari RK. Venezuelan equine encephalitis virus infection causes modulation of inflammatory and immune response genes in mouse brain.. BMC Genomics 2008 Jun 16;9:289.
      doi: 10.1186/1471-2164-9-289pubmed: 18558011google scholar: lookup
    29. Couderc T, Chrétien F, Schilte C, Disson O, Brigitte M, Guivel-Benhassine F, Touret Y, Barau G, Cayet N, Schuffenecker I, Desprès P, Arenzana-Seisdedos F, Michault A, Albert ML, Lecuit M. A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease.. PLoS Pathog 2008 Feb 8;4(2):e29.
      doi: 10.1371/journal.ppat.0040029pubmed: 18282093google scholar: lookup
    30. Konopka JL, Penalva LO, Thompson JM, White LJ, Beard CW, Keene JD, Johnston RE. A two-phase innate host response to alphavirus infection identified by mRNP-tagging in vivo.. PLoS Pathog 2007 Dec;3(12):e199.
      doi: 10.1371/journal.ppat.0030199pubmed: 18215114google scholar: lookup
    31. Castorena KM, Peltier DC, Peng W, Miller DJ. Maturation-dependent responses of human neuronal cells to western equine encephalitis virus infection and type I interferons.. Virology 2008 Mar 1;372(1):208-20.
      doi: 10.1016/j.virol.2007.10.025pubmed: 18022665google scholar: lookup
    32. Zhang Y, Burke CW, Ryman KD, Klimstra WB. Identification and characterization of interferon-induced proteins that inhibit alphavirus replication.. J Virol 2007 Oct;81(20):11246-55.
      doi: 10.1128/JVI.01282-07pubmed: 17686841google scholar: lookup
    33. Aguilar PV, Weaver SC, Basler CF. Capsid protein of eastern equine encephalitis virus inhibits host cell gene expression.. J Virol 2007 Apr;81(8):3866-76.
      doi: 10.1128/JVI.02075-06pubmed: 17267491google scholar: lookup
    34. Haller O, Kochs G, Weber F. The interferon response circuit: induction and suppression by pathogenic viruses.. Virology 2006 Jan 5;344(1):119-30.
      doi: 10.1016/j.virol.2005.09.024pubmed: 16364743google scholar: lookup
    35. Samuel MA, Diamond MS. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival.. J Virol 2005 Nov;79(21):13350-61.
      doi: 10.1128/JVI.79.21.13350-13361.2005pubmed: 16227257google scholar: lookup
    36. Aguilar PV, Paessler S, Carrara AS, Baron S, Poast J, Wang E, Moncayo AC, Anishchenko M, Watts D, Tesh RB, Weaver SC. Variation in interferon sensitivity and induction among strains of eastern equine encephalitis virus.. J Virol 2005 Sep;79(17):11300-10.
      doi: 10.1128/JVI.79.17.11300-11310.2005pubmed: 16103182google scholar: lookup
    37. Vogel P, Kell WM, Fritz DL, Parker MD, Schoepp RJ. Early events in the pathogenesis of eastern equine encephalitis virus in mice.. Am J Pathol 2005 Jan;166(1):159-71.
      doi: 10.1016/S0002-9440(10)62241-9pubmed: 15632009google scholar: lookup
    38. Novelli F, Casanova JL. The role of IL-12, IL-23 and IFN-gamma in immunity to viruses.. Cytokine Growth Factor Rev 2004 Oct;15(5):367-77.
      doi: 10.1016/j.cytogfr.2004.03.009pubmed: 15450252google scholar: lookup
    39. Anishchenko M, Paessler S, Greene IP, Aguilar PV, Carrara AS, Weaver SC. Generation and characterization of closely related epizootic and enzootic infectious cDNA clones for studying interferon sensitivity and emergence mechanisms of Venezuelan equine encephalitis virus.. J Virol 2004 Jan;78(1):1-8.
      doi: 10.1128/jvi.78.1.1-8.2004pubmed: 14671082google scholar: lookup
    40. Perri S, Greer CE, Thudium K, Doe B, Legg H, Liu H, Romero RE, Tang Z, Bin Q, Dubensky TW Jr, Vajdy M, Otten GR, Polo JM. An alphavirus replicon particle chimera derived from venezuelan equine encephalitis and sindbis viruses is a potent gene-based vaccine delivery vector.. J Virol 2003 Oct;77(19):10394-403.
      doi: 10.1128/jvi.77.19.10394-10403.2003pubmed: 12970424google scholar: lookup
    41. Samuel CE. Antiviral actions of interferons.. Clin Microbiol Rev 2001 Oct;14(4):778-809, table of contents.
      doi: 10.1128/CMR.14.4.778-809.2001pubmed: 11585785google scholar: lookup
    42. Johnston C, Jiang W, Chu T, Levine B. Identification of genes involved in the host response to neurovirulent alphavirus infection.. J Virol 2001 Nov;75(21):10431-45.
      doi: 10.1128/JVI.75.21.10431-10445.2001pubmed: 11581411google scholar: lookup
    43. White LJ, Wang JG, Davis NL, Johnston RE. Role of alpha/beta interferon in Venezuelan equine encephalitis virus pathogenesis: effect of an attenuating mutation in the 5' untranslated region.. J Virol 2001 Apr;75(8):3706-18.
      doi: 10.1128/JVI.75.8.3706-3718.2001pubmed: 11264360google scholar: lookup
    44. Lukaszewski RA, Brooks TJ. Pegylated alpha interferon is an effective treatment for virulent venezuelan equine encephalitis virus and has profound effects on the host immune response to infection.. J Virol 2000 Jun;74(11):5006-15.
      doi: 10.1128/jvi.74.11.5006-5015.2000pubmed: 10799574google scholar: lookup
    45. Price GE, Gaszewska-Mastarlarz A, Moskophidis D. The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice.. J Virol 2000 May;74(9):3996-4003.
      doi: 10.1128/jvi.74.9.3996-4003.2000pubmed: 10756011google scholar: lookup
    46. Byrnes AP, Durbin JE, Griffin DE. Control of Sindbis virus infection by antibody in interferon-deficient mice.. J Virol 2000 Apr;74(8):3905-8.
      doi: 10.1128/jvi.74.8.3905-3908.2000pubmed: 10729167google scholar: lookup
    47. Ryman KD, Klimstra WB, Nguyen KB, Biron CA, Johnston RE. Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism.. J Virol 2000 Apr;74(7):3366-78.
      doi: 10.1128/jvi.74.7.3366-3378.2000pubmed: 10708454google scholar: lookup
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