Skip to content
1887

Journal of General Virology header logo Journal of General Virology

Volume 104, Issue 8

VP24 matrix proteins of eight filoviruses downregulate innate immune response by inhibiting the interferon-induced pathway Open Access

Abstract

Filoviruses encode viral protein 24 (VP24) which effectively inhibit the innate immune responses in infected cells. Here we systematically analysed the effects of nine mammalian filovirus VP24 proteins on interferon (IFN)-induced immune response. We transiently expressed Ebola, Bombali, Bundibugyo, Reston, Sudan and Taï Forest ebolavirus (EBOV, BOMV, BDBV, RESTV, SUDV, TAFV, respectively), Lloviu virus (LLOV), Mengla dianlovirus (MLAV) and Marburgvirus (MARV) VP24 proteins and analysed their ability to inhibit IFN-α-induced activation of myxovirus resistance protein 1 (MxA) and interferon-induced transmembrane protein 3 (IFITM3) promoters. In addition, we analysed the expression of endogenous MxA protein in filovirus VP24-expressing cells. Eight filovirus VP24 proteins, including the VP24s of the recently discovered MLAV, BOMV and LLOV, inhibited IFN-induced MxA and IFITM3 promoter activation. MARV VP24 was the only protein with no inhibitory effect on the activation of either promoter. Endogenous MxA protein expression was impaired in cells transiently expressing VP24s with the exception of MARV VP24. We mutated nuclear localization signal (NLS) of two highly pathogenic filoviruses (EBOV and SUDV) and two putatively non-pathogenic filoviruses (BOMV and RESTV), and showed that the inhibitory effect on IFN-induced expression of MxA was dependent on functional cluster 3 of VP24 nuclear localization signal. Our findings suggest that filovirus VP24 proteins are both genetically and functionally conserved, and that VP24 proteins of most filovirus species are capable of inhibiting IFN-induced antiviral gene expression thereby efficiently downregulating the host innate immune responses.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): filovirus , IFITM3 , innate immunity , interferon , MxA , nuclear localization signal and VP24
Funding
This study was supported by the:
  • Jane ja Aatos Erkon Säätiö
    • Principle Award Recipient: IlkkaJulkunen
  • Sigrid Juséliuksen Säätiö
    • Principle Award Recipient: IlkkaJulkunen
  • Academy of Finland (Award Academy of Finland (297329 and 339512))
    • Principle Award Recipient: IlkkaJulkunen
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001888
2023-08-30
2025-05-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/104/8/jgv001888.html?itemId=/content/journal/jgv/10.1099/jgv.0.001888&mimeType=html&fmt=ahah

References

  1. Feldmann H, Jones S, Klenk H-D, Schnittler H-J. Ebola virus: from discovery to vaccine. Nat Rev Immunol 2003; 3:677–685 [View Article] [PubMed]
     [Google Scholar]
  2. Carroll SA, Towner JS, Sealy TK, McMullan LK, Khristova ML et al. Molecular evolution of viruses of the family Filoviridae based on 97 whole-genome sequences. J Virol 2013; 87:2608–2616 [View Article] [PubMed]
     [Google Scholar]
  3. Amarasinghe GK, Aréchiga Ceballos NG, Banyard AC, Basler CF, Bavari S et al. Taxonomy of the order Mononegavirales: update 2018. Arch Virol 2018; 163:2283–2294 [View Article] [PubMed]
     [Google Scholar]
  4. Bukreyev AA, Chandran K, Dolnik O, Dye JM, Ebihara H et al. Discussions and decisions of the 2012–2014 International Committee on Taxonomy of Viruses (ICTV) filoviridae study group, January 2012–June 2013. Arch Virol 2014; 159:821–830 [View Article] [PubMed]
     [Google Scholar]
  5. Kuhn JH, Becker S, Ebihara H, Geisbert TW, Johnson KM et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol 2010; 155:2083–2103 [View Article] [PubMed]
     [Google Scholar]
  6. Lam WK, Zhong NS, Tan WC. Overview on SARS in Asia and the world. Respirology 2003; 8 Suppl:S2–5 [View Article] [PubMed]
     [Google Scholar]
  7. McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol 2015; 15:87–103 [View Article] [PubMed]
     [Google Scholar]
  8. Au-Yeung N, Mandhana R, Horvath CM. Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway. JAKSTAT 2013; 2:e23931 [View Article] [PubMed]
     [Google Scholar]
  9. Mühlberger E. Filovirus replication and transcription. Future Virol 2007; 2:205–215 [View Article] [PubMed]
     [Google Scholar]
  10. Basler CF. Innate immune evasion by filoviruses. Virology 2015; 479–480:122–130 [View Article] [PubMed]
     [Google Scholar]
  11. Messaoudi I, Amarasinghe GK, Basler CF. Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus. Nat Rev Microbiol 2015; 13:663–676 [View Article] [PubMed]
     [Google Scholar]
  12. Xu W, Edwards MR, Borek DM, Feagins AR, Mittal A et al. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 2014; 16:187–200 [View Article] [PubMed]
     [Google Scholar]
  13. Feagins AR, Basler CF. Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells. Virology 2015; 485:145–152 [View Article] [PubMed]
     [Google Scholar]
  14. Schwarz TM, Edwards MR, Diederichs A, Alinger JB, Leung DW et al. VP24-Karyopherin alpha binding affinities differ between Ebolavirus species, influencing interferon inhibition and VP24 stability. J Virol 2017; 91:e01715-16 [View Article] [PubMed]
     [Google Scholar]
  15. Valmas C, Grosch MN, Schümann M, Olejnik J, Martinez O et al. Marburg virus evades interferon responses by a mechanism distinct from ebola virus. PLoS Pathog 2010; 6:e1000721 [View Article] [PubMed]
     [Google Scholar]
  16. Williams CG, Gibbons JS, Keiffer TR, Luthra P, Edwards MR et al. Impact of Měnglà virus proteins on Human and Bat innate immune pathways. J Virol 2020; 94:e00191-20 [View Article] [PubMed]
     [Google Scholar]
  17. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994; 22:4673–4680 [View Article] [PubMed]
     [Google Scholar]
  18. Tamura K, Stecher G, Kumar S. MEGA11: Molecular Evolutionary Genetics Analysis version 11. Mol Biol Evol 2021; 38:3022–3027 [View Article] [PubMed]
     [Google Scholar]
  19. He F, Melén K, Maljanen S, Lundberg R, Jiang M et al. Ebolavirus protein VP24 interferes with innate immune responses by inhibiting interferon-λ1 gene expression. Virology 2017; 509:23–34 [View Article] [PubMed]
     [Google Scholar]
  20. Ronni T, Melén K, Malygin A, Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol 1993; 150:1715–1726 [PubMed]
     [Google Scholar]
  21. He FB, Khan H, Huttunen M, Kolehmainen P, Melén K et al. Filovirus VP24 proteins differentially regulate RIG-I and MDA5-dependent type I and III interferon promoter activation. Front Immunol 2021; 12:694105 [View Article] [PubMed]
     [Google Scholar]
  22. Reid SP, Leung LW, Hartman AL, Martinez O, Shaw ML et al. Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J Virol 2006; 80:5156–5167 [View Article] [PubMed]
     [Google Scholar]
  23. Negredo A, Palacios G, Vázquez-Morón S, González F, Dopazo H et al. Discovery of an ebolavirus-like filovirus in europe. PLoS Pathog 2011; 7:e1002304 [View Article] [PubMed]
     [Google Scholar]
  24. Goldstein T, Anthony SJ, Gbakima A, Bird BH, Bangura J et al. The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. Nat Microbiol 2018; 3:1486 [View Article] [PubMed]
     [Google Scholar]
  25. Yang X-L, Tan CW, Anderson DE, Jiang R-D, Li B et al. Characterization of a filovirus (Měnglà virus) from Rousettus bats in China. Nat Microbiol 2019; 4:543 [View Article] [PubMed]
     [Google Scholar]
  26. Pappalardo M, Reddin IG, Cantoni D, Rossman JS, Michaelis M et al. Changes associated with Ebola virus adaptation to novel species. Bioinformatics 2017; 33:1911–1915 [View Article] [PubMed]
     [Google Scholar]
  27. Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res 2011; 31:79–87 [View Article] [PubMed]
     [Google Scholar]
  28. Spence JS, He R, Hoffmann H-H, Das T, Thinon E et al. IFITM3 directly engages and shuttles incoming virus particles to lysosomes. Nat Chem Biol 2019; 15:259–268 [View Article] [PubMed]
     [Google Scholar]
  29. Dunham EC, Banadyga L, Groseth A, Chiramel AI, Best SM et al. Assessing the contribution of interferon antagonism to the virulence of West African Ebola viruses. Nat Commun 2015; 6:8000 [View Article] [PubMed]
     [Google Scholar]
  30. Fanunza E, Iampietro M, Distinto S, Corona A, Quartu M et al. Quercetin blocks Ebola virus infection by counteracting the VP24 interferon-inhibitory function. Antimicrob Agents Chemother 2020; 64:e00530-20 [View Article] [PubMed]
     [Google Scholar]
/content/journal/jgv/10.1099/jgv.0.001888
Loading
VP24 matrix proteins of eight filoviruses downregulate innate immune response by inhibiting the interferon-induced pathway
J. Gen. Virol. 104, 001888 (2023); https://doi.org/10.1099/jgv.0.001888
/content/journal/jgv/10.1099/jgv.0.001888
/content/journal/jgv/10.1099/jgv.0.001888
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error