Torque teno viruses (TTVs) are one of the most common constituents of the human virome and almost all metagenomics studies report TTVs as the most abundant viruses in human blood. TTVs are non-enveloped, with a capsid diameter of ~30nm and have a single strand, negative sense DNA genome. These viruses infect humans and several animal species, but despite their high-genetic diversity, all TTVs share a highly conserved 100-130 nt long untranslated region. Phylogenetic analysis of TTV variants found in different host species suggest their species specificity, but experimental infection studies to rule out cross-species transmission are not reported, except in chimpanzees. Despite being a common and persistent virus infection of humans, the biological characteristics and health relevance of TTVs remain largely unknown due to the lack of an informative animal model or cell culture system. A tractable and genetically amenable model for TTVs infection can shed new light on the biological properties and health relevance of these common viruses. Our efforts to infect immunocompetent and immunocompromised mice with human TTVs were unsuccessful. Animal homologs of human viruses can provide informative surrogate models to study virus infection, immunity and pathogenesis. Some examples are Simian Immunodeficiency virus, murine cytomegaloviruses, murine norovirus, woodchuck hepatitis B virus and rat hepatitis C-like virus. We therefore looked for TTVs in feral mice, rats and other rodent species. Interestingly, no TTVs were found in feral mice (Mus musculus), but several genotypes of TTVs were found in feral rats of two different, yet closely related species, Rattus norvegicus and Rattus rattus. Here, we propose to use these feral rat viruses to develop tractable murine models for TTVs infection and propose two specific aims for this exploratory project.
Aim -1 is to study the basic biological properties of rat TTVs in inbred and outbred laboratory rats. We will study the nature of their infection (acute or chronic), transmission, tissue tropism and species specificity.
Aim -2 is to study the health relevance of TTV infection by characterizing antiviral host responses. We will analyze functional virus-specific T-cell responses, cytokines and will also use RNA-seq analysis of virus-infected tissues to study the host transcriptional changes induced by TTV infection. A well- characterized, tractable and genetically amenable murine model for TTV, one of the most common human virus infections, will help aid our understanding of their biological properties and health relevance.
Despite being a common and persistent virus infection of humans, the biological characteristics and health relevance of Torque teno viruses (TTVs) remain largely unknown due to lack of an informative animal model or cell culture system. We will develop a well-characterized, tractable and genetically amenable murine model for TTVs, as this new model will help in understanding their infection, transmission, and pathogenesis and health relevance.
