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HEIndividual fellowship2023–2025

EpiCoVs · The tRNA epitranscriptome: a novel player in viral infections

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-05-01 → 2025-04-30
EU contribution
€181,153
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

The tRNA epitranscriptome: a novel player in viral infections

A long-standing question in virology is how viruses with suboptimal codon usage can efficiently produce high levels of proteins during infection. The EpiCoVs project set out to address this paradox using coronaviruses as a model, since their genomes are significantly enriched in A/U-ending codons, which are considered rare in the host G/C-rich translational environment. The central hypothesis of the project was that coronaviruses manipulate the host tRNA epitranscriptome, specifically by inducing targeted tRNA modifications, to reprogram translation in a codon-specific manner that favors viral protein synthesis. We proposed that this strategy is a conserved mechanism among multiple coronavirus species, enabling them to fine-tune host translation machinery to their own codon usage. Importantly, this mechanism could represent a novel target for the development of broad-spectrum antiviral therapies. This hypothesis was supported by: 1. The observation that coronavirus genomes are consistently enriched in codons typically considered rare in mammalian cells. 2. Coronaviruses replicate very efficiently despite their enrichment in suboptimal codons. 2. Preliminary results from the laboratory showing that at least one tRNA-modifying enzyme, KIAA1456, is strongly upregulated in DENV and CHIKV infected cells, that are positive strand RNA viruses like coronaviruses. In the broader context of the COVID-19 pandemic and the EU strategic focus on pandemic preparedness, this research addressed a critical and previously underexplored aspect of host-virus interactions. EpiCoVs aimed to identify conserved, coronavirus-induced changes in tRNA modifications and the enzymes responsible, to assess whether these changes support viral protein synthesis and contribute to pathogenicity. To achieve this, the project focused on both highly pathogenic viruses (using SARS-CoV-2) and mildly pathogenic strains (such as HCoV-OC43). Overall, the findings establish a new conceptual framework for virus-host interactions and lay the foundation for innovative antiviral strategies with broad applicability.

Data: CORDIS, © European Union

Project objective

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.

Original text from CORDIS.

Participants

  • UNIVERSIDAD POMPEU FABRA · BarcelonaCoordinatorSpain

Links

Data: CORDIS, © European Union