Functional comparison of the NSs virulence factors from the genus Phlebovirus

Research area: Molecular Virology

The genus Phlebovirus (family Phenuiviridae, order Bunyavirales) contains virus species covering a wide spectrum of virulence. Rift Valley fever virus (RVFV) is highly pathogenic representative, whereas the Sandfly fever Sicilian virus (SFSV) displays an intermediate level of virulence. Although the importance of phleboviruses is increasingly recognized, we are only beginning to understand the mechanisms of pathogenicity. A key virulence factor of phleboviruses is the non-structural protein NSs, an inhibitor of the antiviral type I interferon (IFN) system. In the previous two funding periods, the Weber group identified the mechanisms by which the NSs proteins of both RVFV and SFSV inhibit the transactivation of the IFN genes and abrogate the antiviral protein kinase R (PKR) pathway. For RVFV, the NSs was found to recruit several E3 ubiquitin ligases of the F-Box type in order to destroy the general host cell transcription factor TF-IIH and the antiviral mRNA translation inhibitor PKR. SFSV NSs, by contrast, is occluding the DNA-binding domain of the IFN transcription factor IRF-3 to inhibit IFN induction, and also binds to the translation initiation factor eIF2B to protect the ribosomal machinery against the inhibitory PKR signaling. Expectedly, phleboviruses with a deleted NSs gene are strong activators of the IFN system. Using an NSs-deleted RVFV, the viral panhandle was identified the main trigger of IFN induction, RIG-I as its cytoplasmic sensor, and the full set of upregulated innate immunity genes was characterized by transcriptome analysis.

Project-related publications of the investigator:

  • Wuerth JD, Weber F. 2022. Shielding the mRNA-translation factor eIF2B from inhibitory p-eIF2 as a viral strategy to evade protein kinase R-mediated innate immunity. Curr Opin Immunol 78:102251.
  • Shalamova L, Felgenhauer U, Wilhelm J, Schaubmar AR, Buettner K, Schoen A, Widera M, Ciesek S, Weber F. 2022. Omicron variant of SARS-CoV-2 exhibits an increased resilience to the antiviral type I interferon response. PNAS Nexus 1:67.
  • Hufsky F, Beslic D, Boeckaerts D, Duchene S, Gonzalez-Tortuero E, Gruber AJ, Guo J, Jansen D, Juma J, Kongkitimanon K, Luque A, Ritsch M, Lencioni Lovate G, Nishimura L, Pas C, Domingo E, Hodcroft E, Lemey P, Sullivan MB, Weber F, Gonzalez-Candelas F, Krautwurst S, Perez-Cataluna A, Randazzo W, Sanchez G, Marz M. 2022. The International Virus Bioinformatics Meeting 2022. Viruses 14.
  • Hollidge BS, Salzano MV, Ibrahim JM, Fraser JW, Wagner V, Leitner NE, Weiss SR, Weber F, Gonzalez-Scarano F, Soldan SS. 2022. Targeted Mutations in the Fusion Peptide Region of La Crosse Virus Attenuate Neuroinvasion and Confer Protection against Encephalitis. Viruses 14.
  • Wuerth JD, Weber F. 2021. NSs of the mildly virulent sandfly fever Sicilian virus is unable to inhibit interferon signaling and upregulation of interferon-stimulated genes. J Gen Virol 102.
  • Kashiwagi K, Shichino Y, Osaki T, Sakamoto A, Nishimoto M, Takahashi M, Mito M, Weber F, Ikeuchi Y, Iwasaki S, Ito T. 2021. eIF2B-capturing viral protein NSs suppresses the integrated stress response. Nat Commun 12:7102.
  • Borrego B, Moreno S, de la Losa N, Weber F, Brun A. 2021. The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice. Viruses 13.
  • Wuerth JD, Habjan M, Kainulainen M, Berisha B, Bertheloot D, Superti-Furga G, Pichlmair A, Weber F. 2020. eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition. mBio 11.
  • Schoen A, Lau S, Verbruggen P, Weber F. 2020. Elongin C Contributes to RNA Polymerase II Degradation by the Interferon Antagonist NSs of La Crosse Orthobunyavirus. J Virol 94.
  • Lau S, Weber F. 2020. Nuclear pore protein Nup98 is involved in replication of Rift Valley fever virus and nuclear import of virulence factor NSs. J Gen Virol 101:712-716.
  • Barr, JD, Weber F., Schmaljohn CS. 2020. Bunyaviruses. Chapter 17, Fields Virology, 7th edition. Lippincott Williams & Wilkins – Philadelphia, USA.
  • Wuerth JD, Weber F. 2019. Ferreting out viral pathogenesis. Nat Microbiol 4:384-385.
  • Jones R, Lessoued S, Meier K, Devignot S, Barata-Garcia S, Mate M, Bragagnolo G, Weber F, Rosenthal M, Reguera J. 2019. Structure and function of the Toscana virus cap-snatching endonuclease. Nucleic Acids Res 47:10914-10930.
  • Holzer M, Schoen A, Wulle J, Muller MA, Drosten C, Marz M, Weber F. 2019. Virus- and Interferon Alpha-Induced Transcriptomes of Cells from the Microbat Myotis daubentonii. iScience 19:647-661.
  • Frantz R, Teubner L, Schultze T, La Pietra L, Muller C, Gwozdzinski K, Pillich H, Hain T, Weber-Gerlach M, Panagiotidis GD, Mostafa A, Weber F, Rohde M, Pleschka S, Chakraborty T, Abu Mraheil M. 2019. The secRNome of Listeria monocytogenes Harbors Small Noncoding RNAs That Are Potent Inducers of Beta Interferon. mBio 10.
  • Wuerth JD, Habjan M, Wulle J, Superti-Furga G, Pichlmair A, Weber F. 2018. NSs Protein of Sandfly Fever Sicilian Phlebovirus Counteracts Interferon (IFN) Induction by Masking the DNA-Binding Domain of IFN Regulatory Factor 3. J Virol 92.
  • Kiening M, Weber F, Frishman D. 2017. Conserved RNA structures in the intergenic regions of ambisense viruses. Sci Rep 7:16625.
  • Ferron F, Weber F, de la Torre JC, Reguera J. 2017. Transcription and replication mechanisms of Bunyaviridae and Arenaviridae L proteins. Virus Res 234:118-134.