The tRNA epitranscriptome: a novel player in viral infections

Recent evidence indicates that codon usage bias regulates gene expression, as synonymous codons are not decoded with the same efficiency. Viruses are entirely dependent on the host translation machinery to express their proteins. Puzzlingly, the genomes of diverse viruses synthesize viral proteins at high levels, such as those of the emerging Chikungunya virus (CHIKV), dengue virus (DENV) and the pandemic SARS-CoV-2 are enriched in rare codons that should slow down their translation. How these viruses achieve this high protein expression remains a fundamental question in virology. In Juana Díez's laboratory, recent findings have revealed an unprecedented interplay of the Chikungunya virus (CHIKV) with the host tRNA epitranscriptome. CHIKV adapts the host translational machinery toward viral codon usage by overexpressing a tRNA modification enzyme that favors translating a specific set of codons enriched in CHIKV RNA. The proposed project will combine cellular, and molecular biology approaches with -omics analyses to further develop this novel research area and explore its translatability. First, using SARS-CoV-2 as a model, we will study whether the observed CHIKV-induced codon-specific reprogramming of the host translation machinery represents a common mechanism to optimize viral protein expression. Second, we will characterize the tRNA modifying enzymes involved. Third, we will explore the antiviral therapeutic interest of the identified enzymes. Together, these findings will shed light on a novel layer of virus-host interaction and might provide a rationale to consider the regulation of the host tRNA epitranscriptome as a promising target for the development of broad-spectrum antivirals.