Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro

Nicolas Ruggli, Artur Summerfield, Ana R. Fiebach, Laurence Guzylack-Piriou, Oliver Bauhofer, Catherine G. Lamm, Sandro Waltersperger, Keita Matsuno, Luzia Liu, Markus Gerber, Kyung Choi, Martin A. Hofmann, Yoshihiro Sakoda, Jon Duri Tratschin

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Abstract

Pestiviruses prevent alpha/beta interferon (IFN-α/β) production by promoting proteasomal degradation of interferon regulatory factor 3 (IRF3) by means of the viral Npro nonstructural protein. Npro is also an autoprotease, and its amino-terminal coding sequence is involved in translation initiation. We previously showed with classical swine fever virus (CSFV) that deletion of the entire Npro gene resulted in attenuation in pigs. In order to elaborate on the role of the Npro-mediated IRF3 degradation in classical swine fever pathogenesis, we searched for minimal amino acid substitutions in Npro that would specifically abrogate this function. Our mutational analyses showed that degradation of IRF3 and autoprotease activity are two independent but structurally overlapping functions of Npro. We describe two mutations in Npro that eliminate Npro-mediated IRF3 degradation without affecting the autoprotease activity. We also show that the conserved standard sequence at these particular positions is essential for Npro to interact with IRF3. Surprisingly, when these two mutations are introduced independently in the backbones of highly and moderately virulent CSFV, the resulting viruses are not attenuated, or are only partially attenuated, in 8- to 10-week-old pigs. This contrasts with the fact that these mutant viruses have lost the capacity to degrade IRF3 and to prevent IFN-α/β induction in porcine cell lines and monocyte-derived dendritic cells. Taken together, these results demonstrate that contrary to previous assumptions and to the case for other viral systems, impairment of IRF3-dependent IFN-α/β induction is not a prerequisite for CSFV virulence.

Original languageEnglish (US)
Pages (from-to)817-829
Number of pages13
JournalJournal of Virology
Volume83
Issue number2
DOIs
StatePublished - Jan 2009

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Interferon Regulatory Factor-3
Classical swine fever virus
Swine
degradation
swine
Viral Nonstructural Proteins
Pestivirus
Classical Swine Fever
interferon-beta
Viruses
mutation
viruses
hog cholera
Mutation
Conserved Sequence
Interferon-beta
amino acid substitution
Amino Acid Substitution
dendritic cells
interferon regulatory factor-3

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Ruggli, N., Summerfield, A., Fiebach, A. R., Guzylack-Piriou, L., Bauhofer, O., Lamm, C. G., ... Tratschin, J. D. (2009). Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro Journal of Virology, 83(2), 817-829. https://doi.org/10.1128/JVI.01509-08

Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro . / Ruggli, Nicolas; Summerfield, Artur; Fiebach, Ana R.; Guzylack-Piriou, Laurence; Bauhofer, Oliver; Lamm, Catherine G.; Waltersperger, Sandro; Matsuno, Keita; Liu, Luzia; Gerber, Markus; Choi, Kyung; Hofmann, Martin A.; Sakoda, Yoshihiro; Tratschin, Jon Duri.

In: Journal of Virology, Vol. 83, No. 2, 01.2009, p. 817-829.

Research output: Contribution to journalArticle

Ruggli, N, Summerfield, A, Fiebach, AR, Guzylack-Piriou, L, Bauhofer, O, Lamm, CG, Waltersperger, S, Matsuno, K, Liu, L, Gerber, M, Choi, K, Hofmann, MA, Sakoda, Y & Tratschin, JD 2009, 'Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro ', Journal of Virology, vol. 83, no. 2, pp. 817-829. https://doi.org/10.1128/JVI.01509-08
Ruggli, Nicolas ; Summerfield, Artur ; Fiebach, Ana R. ; Guzylack-Piriou, Laurence ; Bauhofer, Oliver ; Lamm, Catherine G. ; Waltersperger, Sandro ; Matsuno, Keita ; Liu, Luzia ; Gerber, Markus ; Choi, Kyung ; Hofmann, Martin A. ; Sakoda, Yoshihiro ; Tratschin, Jon Duri. / Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro In: Journal of Virology. 2009 ; Vol. 83, No. 2. pp. 817-829.
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