The Role of Trim Proteins in Regulating Norovirus Replication and Tropism

Viral tropism, or the range of cells, tissues, or species that a virus can infect, is an important concept to understand viral pathogenesis and the emergence of new viral diseases. Noroviruses are the leading cause of diarrheal diseases worldwide, yet little is known about what contributes to norovirus tropism. Filling in this knowledge gap is crucial to better comprehend norovirus biology, pathogenesis, and therapeutic options. Human noroviruses do not robustly replicate in small animal models and thus murine norovirus (MNV) has emerged as a model system to discover mechanisms of norovirus biology and tropism. Over the past several years, it has been established that MNV strains can infect different cells and tissues in mice despite similar routes of inoculation. The molecular basis for these tropism differences are largely unknown. We recently demonstrated that CD300lf is a universal MNV receptor. This finding demonstrates that the primary mechanism for diversifying MNV strain tropism is not differential receptor utilization. These findings suggest the possibility that unknown host antiviral proteins function as restriction factors that limit the tissue and cellular replication of certain MNV strains. Yet, restriction factors for any norovirus have defied molecular identification. Here, we build upon our initial identification of Trim7 and Trim47 as MNV restriction factors. TRIM proteins are ubiquitin E3 ligases, although the substrates and antiviral mechanisms of Trim7 and Trim47 are currently unknown. While Trim7 broadly inhibits MNV strains from replicating, Trim47 selectively inhibits certain MNV strains. In other viral systems, TRIM proteins are responsible for shaping the cellular and species tropism of viruses. Therefore, we hypothesize that Trim7 and Trim47 constitute a family of TRIM restriction factors that regulate the tropism of noroviruses, including human norovirus. In Specific Aim 1, we will determine the molecular mechanism of Trim7 and Trim47 inhibition of MNV. We will also determine the breadth of the antiviral activity of Trim7 and Trim47 on related viruses, including human norovirus. In Specific Aim 2, we will define the physiological role of Trim7 and Trim47 in shaping the cells and tissues that are permissive for MNV replication in vivo. We will also determine the in vivo fitness tradeoffs for viruses that acquire resistance to Trim7 and Trim47 .This project leverages the MNV model system to uncover new mechanisms of viral restriction by a pair of poorly understood TRIM proteins. It will provide insight into drivers of norovirus tropism and evolution.