Professor Mart Ustav, University of Tartu
Volker Lohmann, Heidelberg University, Germany
Essentially every living organism studied thus far may serve as a host for the infection and propagation of species-specific RNA viruses. An infectious virus particle, i.e. a virion, carries the genome in the form of nucleic acid surrounded by a protein or protein-lipid coat.
RNA virus genome replication is driven by the viral genome-encoded RNA-dependent RNA polymerase (RdRp). More specifically, viral RNA genome replication is performed by a replicase, a multisubunit enzyme complex that possesses a core component with RdRp activity. RdRp first utilizes a viral RNA genome template to catalyze the synthesis of complementary RNA, which subsequently serves as a template for the production of viral genomes. RdRp is a molecular machine that transfers the genetic information embedded in genetic material from one RNA molecule to another. All RNA viruses encode the RdRp component of the replicase because host cells either cannot replicate long RNA genomes of viruses (e.g., invertebrates and plants) or do not possess intrinsic RdRp (e.g., vertebrates). Hepatitis delta virus, a satellite virus, is an exception to this rule. In addition to RdRp, all of the other protein subunits required for replicase assembly are encoded by either the viral RNA genome or the host genome.
This dissertation involved a journey from the test tube to the host cell to analyze the effects of the viral RdRp activities of "yellow" and "mantled" RNA viruses of Flaviviridae and Togaviridae families. First, we performed structure-function relationship analyses of the hepatitis C virus (HCV) core RdRp component in different molecular environments. Second, by conducting Semliki Forest virus (SFV) replication studies, we found that the SFV replicase not only replicates viral nucleic acids but also has the capacity to transcribe host cell RNA templates. The latter "side effect" of SFV replicase RdRp activity triggers a potent cellular antiviral response. This finding led to the development of a generalized novel model that describes how vertebrate host cells might detect RNA viruses similar to SFV and how viruses counteract this detection.