Project Portugal 2030

Summary

ModiVir aims to validate tRNA epitranscriptome reprograming as an antiviral therapeutic approach. Although ambitious, our hypothesis is supported by our preliminary data showing that the tRNA epitranscriptome is modulated upon viral infection, and that tackling the host translation machinery represents a promising antiviral strategy (see Annex – 1. Preliminary data). The implementation of this multidisciplinary project relies on a team that gathers experts across multiple disciplines, including tRNA biology and molecular biotechnology, virology and innate immunity, groundbreaking epitranscriptomics, genomics and bioinformatics. By exploring the relatively uncharted territory of host tRNA epitranscriptome reprograming as an antiviral strategy, this project will make unprecedent scientific advances in both RNA biology, epitranscriptome and virology, contributing to: 1) Uncover the tRNA epitranscriptome dynamics landscape upon viral infection and elucidate whether it is virus-specific 2) Elucidate what are the implications of viral-induced tRNA epitranscriptome dynamics for host and viral translation 3) Uncover the molecular mechanisms underlying tRNA epitranscriptome modulation and its cellular implications in the context of viral infections and host immune antiviral responses 4) Validate the antiviral potential of targeting the host tRNA epitranscriptome machinery by a combination of gene- and RNA-based strategies. ModiVir will define the host tRNA epitranscriptome specific signature upon infection with different RNA respiratory viruses (IAV, RSV, HCoV-229E), with high-throughput epitranscriptomic quantification methodologies developed and used by our team. The impact of this virus-induced host tRNA dynamics on gene expression will be assessed at the mRNA translation level by a combination of state-of-the-art tRNA profiling, RNA-Seq and Ribo-Seq. By disrupting the tRNA epitranscriptome by overexpressing or knocking down tRNA epitranscriptome machinery components, we will decipher the mechanisms governing tRNA epitranscriptome dynamics upon infection and its biological relevance for both viral replication and host immune responses. The integration of all the data will define which tRNA modifications can be explored to develop targeted antiviral approaches. Finally, we will develop a screening platform that will allow to test the antiviral potential of reprograming the host tRNA epitranscriptome with a combination of gene and RNA-based therapies using 3D in vitro models of disease to evaluate to what extent this can be used as an antiviral strategy in a therapeutic setting. ModiVir will provide evidence that tRNA epitranscriptome reprograming can be used as a potent host-directed antiviral strategy and will lead to the development of targeted antiviral solutions that can overcome resistance and side effects common with traditional antiviral strategies directed towards viral components. If successful, the results obtained can be translated in biotechnology applications in the health sector. ModiVir’s approach will disclose the previous overlooked molecular mechanisms governing tRNA epitranscriptome dynamics upon infection and provide solid grounds to develop novel therapeutic strategies that can be extrapolated to other diseases where the epitranscriptome is also affected.