Novel Gene Product of Thogoto Virus Segment 6 Codes for an Interferon Antagonist

Abstract

Thogoto virus (THOV) is a tick-transmitted orthomyxovirus with a genome of six negative-stranded RNA segments. The sixth segment encodes two different transcripts: a spliced transcript that is translated into the matrix protein (M) and an unspliced transcript. Here, we report that the unspliced transcript encodes an elongated form of M named ML. A THOV isolate deficient in ML expression was an efficient interferon inducer, whereas ML-expressing wild-type strains were poor interferon inducers. These results were confirmed with recombinant THOVs rescued from cDNAs. Expression of ML efficiently suppressed activation of the beta interferon promoter by double-stranded RNA. These results indicate that ML is an accessory protein that functions as a potent interferon antagonist by blocking transcriptional activation of alpha/beta interferons.

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

“…The mouse Mx1 promoter was chosen instead of the human MxA promoter because the transfected reporter plasmid containing the MxA promoter revealed a strong basal reporter gene expression in various cell lines even without IFN stimulation (data not shown). The 293 human embryonic kidney cells were transiently transfected with 0.5 mg of the plasmid using 2 ml Dac-30 (Eurogentech, Seraing, Belgium) as described [Hagmaier et al, 2003]. Six hours post transfection cells were either treated with recombinant PEG-IFN-a2b or left untreated.…”

Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

“…Further analysis demonstrated that ML associates with IRF7, prevents IRF7 interaction with TRAF6 and blocks IRF7 dimerization, indicating that THOVML can also alter the composition of the pDCspecific signalling pathway and prevent the assembly of a transcriptionally active IRF7 complex. Thus, targeting of the transcription factor IRF7 in addition to IRF3 by ML most probably contributes to the suppression of IFN production by THOV in cell culture and in vivo (Hagmaier et al, 2003;Pichlmair et al, 2004).IRFs consist of an N-terminal DNA-binding domain that shows a homologous structure in the different IRFs and a less conserved C-terminal effector domain that is the target of regulatory modifications and contains the transactivation potential (Mamane et al, 1999). Coimmunoprecipitation of ML together with IRF7 suggests a direct association of ML with this factor.…”

“…In order to avoid the antiviral effects of IFN, THOV developed a strategy to suppress the induction of the IFN system. We have previously shown that the ML protein, an extended version of the viral matrix (M) protein, is a viral IFN antagonist (Hagmaier et al, 2003(Hagmaier et al, , 2004. Previous work with a recombinant THOV lacking ML expression showed that ML is essential for virus growth and pathogenesis in an IFN-competent host (Pichlmair et al, 2004).…”

“…ML blocks the function of IRF3 and IRF7 and is therefore able to interfere with several signal transduction pathways involved in innate immune response. In previous studies we showed that ML suppresses the action of IRF3, the critical factor involved in early type I IFN induction (Jennings et al, 2005) and blocks induction of type I IFN in THOV-infected cells (Hagmaier et al, 2003). However, an incomplete block of IFN synthesis might lead to an amplification of the IFN signal through IRF7.…”

Diversidade genética da neuraminidase de vírus Influenza A, isolados de crianças internadas na cidade de São Paulo, de 1995 a 2006.

“…Os gêneros B e C são restritos aos humanos com raros relatos de isolamento do gênero B, em focas, e do C, em porcos (BOON et al, 2001). O gênero Thogotovirus contém as espécies Dhori virus e Thogo virus, que acometem carrapatos (HAGMAIER et al, 2003) e os Isavirus são importantes patógenos na aquicultura marinha do salmão (FAUQUET et al, 2004;KIBENGE et al, 2001). …”