ABSTRACT
The Thogoto virus ML protein suppresses interferon synthesis in infected cells. Nevertheless, a virus mutant lacking ML remained highly pathogenic in standard laboratory mice. It was strongly attenuated, however, in mice carrying the interferon-responsive Mx1 gene found in wild mice, demonstrating that enhanced interferon synthesis is protective only if appropriate antiviral effector molecules are present. Our study shows that the virulence-enhancing effects of some viral interferon antagonists may escape detection in conventional animal models.
Subject(s)
GTP-Binding Proteins/metabolism , Orthomyxoviridae Infections/physiopathology , Thogotovirus/pathogenicity , Viral Matrix Proteins/metabolism , Virulence Factors/metabolism , Animals , Animals, Newborn , Disease Models, Animal , GTP-Binding Proteins/genetics , Interferons/biosynthesis , Mice , Mice, Inbred BALB C , Mutation , Myxovirus Resistance Proteins , Orthomyxoviridae Infections/virology , Thogotovirus/genetics , Viral Matrix Proteins/genetics , Virulence , Virulence Factors/geneticsABSTRACT
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.
