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1.
Virus Res ; 140(1-2): 15-23, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19041350

ABSTRACT

Interferon (IFN) type-I is of utmost importance in the innate antiviral defence of eukaryotic cells. The cells express intra- and extracellular receptors that monitor their surroundings for the presence of viral genomes. Bovine viral diarrhoea virus (BVDV), a Pestivirus of the family Flaviviridae, is able to prevent IFN synthesis induced by poly(IC), a synthetic dsRNA. The evasion of innate immunity might be a decisive ability of BVDV to establish persistent infection in its host. We report that ds- as well as ssRNA fragments of viral origin are able to trigger IFN synthesis, and that the viral envelope glycoprotein E(rns), that is also secreted from infected cells, is able to inhibit IFN expression induced by these extracellular viral RNAs. The RNase activity of E(rns) is required for this inhibition, and E(rns) degrades ds- and ssRNA at neutral pH. In addition, cells infected with a cytopathogenic strain of BVDV contain more dsRNA than cells infected with the homologous non-cytopathogenic strain, and the intracellular viral RNA was able to excite the IFN system in a 5'-triphosphate-, i.e. RIG-I-, independent manner. Functionally, E(rns) might represent a decoy receptor that binds and enzymatically degrades viral RNA that otherwise might activate the IFN defence by binding to Toll-like receptors of uninfected cells. Thus, the pestiviral RNase efficiently manipulates the host's self-nonself discrimination to successfully establish and maintain persistence and immunotolerance.


Subject(s)
Diarrhea Viruses, Bovine Viral/immunology , Endoribonucleases/metabolism , Interferon Type I/biosynthesis , Membrane Glycoproteins/metabolism , RNA, Double-Stranded/metabolism , Viral Envelope Proteins/metabolism , Animals , Bovine Virus Diarrhea-Mucosal Disease/immunology , Bovine Virus Diarrhea-Mucosal Disease/virology , Cattle , Cell Line , Diarrhea Viruses, Bovine Viral/metabolism , Endoribonucleases/immunology , Interferon Type I/immunology , Membrane Glycoproteins/immunology , Poly I-C/immunology , Poly I-C/pharmacology , RNA, Double-Stranded/immunology , RNA, Viral/immunology , RNA, Viral/metabolism , Viral Envelope Proteins/immunology
2.
J Gen Virol ; 89(Pt 10): 2501-2506, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18796719

ABSTRACT

Recombinant pestivirus envelope glycoprotein E(rns) has been shown to interfere with dsRNA-induced interferon (IFN-alpha/beta) synthesis. This study demonstrated that authentic, enzymically active E(rns) produced in mammalian cells prevented a dsRNA-induced IFN response when present in the supernatant of bovine cells. Strikingly, IFN synthesis of cells expressing E(rns) was eliminated after extracellular addition, but not transfection, of dsRNA. Importantly, the same applied to cells infected with bovine viral diarrhea virus (BVDV) expressing E(rns) but lacking the N-terminal protease N(pro). Free E(rns) concentrations circulating in the blood of animals persistently infected with BVDV were determined to be approximately 50 ng ml(-1), i.e. at a similar order of magnitude as that displaying an effect on dsRNA-induced IFN expression in vitro. Whilst N(pro) blocks interferon regulatory factor-3-dependent IFN induction in infected cells, E(rns) may prevent constant IFN induction in uninfected cells by dsRNA that could originate from pestivirus-infected cells. This probably contributes to the survival of persistently BVDV-infected animals and maintains viral persistence in the host population.


Subject(s)
Diarrhea Viruses, Bovine Viral/pathogenicity , Endoribonucleases/metabolism , Interferons/antagonists & inhibitors , RNA, Double-Stranded/pharmacology , Ribonucleases/metabolism , Viral Envelope Proteins/metabolism , Animals , Cattle , Cell Line , Cytoplasm/metabolism , Diarrhea Viruses, Bovine Viral/metabolism , Endoribonucleases/genetics , Interferons/biosynthesis , RNA, Double-Stranded/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Ribonucleases/genetics , Signal Transduction , Viral Envelope Proteins/genetics , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
3.
Vet Immunol Immunopathol ; 110(1-2): 37-49, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16216336

ABSTRACT

Toll-like receptors are of key importance in the recognition of and response to infectious agents by cells of the innate immune system. TLR mRNA expression and TLR-mediated functions were determined in bovine macrophages (MPhi) infected with bovine viral diarrhea virus (BVDV) or stimulated with interferon-gamma (IFN-gamma) in order to see whether they are correlated under these conditions. As parameters quantitative real time RT-PCR (QRT-PCR) for TLR2, TLR3 and TLR4, NO and TNF production were measured. Triggering of bovine MPhi with bona fide TLR2 and TLR4 agonists (lipopolysaccharide, lipoteichoic acid, peptidoglycan, lipopetide) led to NO and TNF production but neither TLR3 nor TLR9 agonists (double-stranded RNA, CpG DNA) showed this effect. The mRNA expression of TLR2, TLR3 and TLR4 was neither influenced by MPhi costimulation with IFN-gamma nor by MPhi preinfection with BVDV nor by the ligands themselves. However, NO production induced by TLR2 or TLR4 agonists was strongly modulated either by IFN-gamma costimulation or BVDV preinfection. Thus costimulation of MPhi with IFN-gamma resulted in an increase of both NO synthesis and TNF expression by cells stimulated simultaneously by TLR2 or TLR4 agonists. Preinfection of bovine MPhi by BVDV resulted in upregulation of TLR2- and TLR4-mediated NO synthesis. Collectively, these data show that TLR-mediated functions may be modulated by viral infection or activation via IFN-gamma of MPhi whereas the mRNA concentrations of relevant TLR members were not significantly influenced. Thus, the amount of TLR2, TLR3 and TLR4 mRNA transcripts is stable at least under the conditions tested. More importantly, modulation of TLR-mediated responses was dissociated from mRNA expression of TLR members.


Subject(s)
Bovine Virus Diarrhea-Mucosal Disease/immunology , Diarrhea Viruses, Bovine Viral/immunology , Macrophages/immunology , Toll-Like Receptors/agonists , Toll-Like Receptors/immunology , Animals , Bovine Virus Diarrhea-Mucosal Disease/genetics , Bovine Virus Diarrhea-Mucosal Disease/metabolism , Bovine Virus Diarrhea-Mucosal Disease/virology , Cattle , Gene Expression Regulation , Interferon-gamma/pharmacology , Lipopolysaccharides/pharmacology , Macrophage Activation/immunology , Macrophages/metabolism , Macrophages/virology , Nitric Oxide/biosynthesis , Nitric Oxide/immunology , Peptidoglycan/pharmacology , RNA, Double-Stranded/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Teichoic Acids/pharmacology , Toll-Like Receptors/biosynthesis , Toll-Like Receptors/genetics , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/immunology
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