N(pro) of classical swine fever virus prevents type I interferon-mediated priming of conventional dendritic cells for enhanced interferon-α response.
A hallmark of acute classical swine fever is the high interferon (IFN)-α levels found in the serum early after infection, followed by an inflammatory cytokine storm. Plasmacytoid dendritic cells (pDCs) represent the only known cell type that produces IFN-α upon classical swine fever virus (CSFV) infection in vitro. In primary target cells of the virus the viral protein N(pro) inhibits the induction of type I IFN via the degradation of IRF3. We hypothesized that the early systemic pDC-derived IFN-α response sensitizes immune cells for enhanced responsiveness and augment cytokine responses after CSFV infection through the upregulation of IRF7. Therefore, bone marrow-derived granulocyte macrophage-colony stimulating factor (GM-CSF)-induced DCs, were pretreated with IFN-β or conditioned medium from CSFV-activated enriched pDC, and expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and IFN-α was assessed after infection with wild-type CSFV and with an N(pro) mutant [N(pro)(D(136)N)] unable to interact with IRF3 and IRF7. While type I IFN treatment sensitized the DCs for enhanced IFN and cytokine responses after stimulation with influenza virus, lipopolysaccharide or poly(I):poly(C), this was not observed for CSFV. In contrast, the N(pro)(D(136)N) mutant CSFV induced elevated IFN-α responses in type I IFN-pretreated GM-CSF DCs. These results indicate that CSFV has evolved to prevent type I IFN sensitization in infected cells through the action of the N(pro).
Institute of Virology and Immunoprophylaxis, Mittelhäusern, Switzerland.
Linda
L
Hüsser
Nicolas
N
Ruggli
Artur
A
Summerfield
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006691:Classical Swine Fever / Q000276:immunology* / Q000821:virology; D006692:Classical Swine Fever Virus / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013552:Swine / Q000276:immunology* / Q000821:virology; D015854:Up-Regulation / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D007370:Interferon Type I; D016898:Interferon-alpha; D014764:Viral Proteins; D010450:Endopeptidases; C505229:N(pro) protein, swine fever virus