Study Details How Virus Hijacks Host tRNA to Replicate

Researchers in Spain have described a previously unknown mechanism by which viruses modify cellular machinery to maximize their progeny.

Genes contain the information required for the formation of proteins from amino acids. The reading of this information takes place in two main stages: transcription and translation. In translation, the information of the gene (DNA) is transferred to a molecule called messenger RNA (mRNA), which consists of a “text” formed by triplets of nucleotides. Each triplet corresponds to an amino acid. During translation, transfer RNA (tRNA) recognizes each triplet and acts as a translator by bringing the corresponding amino acid. Proteins are built via this process.

There are 61 codons and 20 amino acids, and so many triplets code for the same amino acid. Each organism preferably uses one of these triplets (optimal triplet) because it has a higher concentration of the tRNA that recognizes that triplet. Thus, when the “text” of the mRNA is enriched in optimal triplets, the proteins will be generated quickly and efficiently whereas when they are enriched in non-optimal triplets, the efficiency of the expression will decrease because the related tRNAs are scarce.

To multiply, viruses need to hijack this cellular machinery. Viruses generate their own mRNA in the cells they infect, which the latter read and generate viral proteins to produce more viruses. But the mRNAs of many viruses, including SARS-CoV-2 and viruses transmitted by mosquitoes (i.e., dengue, zika and chikungunya), are enriched in non-optimal triplets and still express viral proteins with great efficacy.

In a study published in Nature Communications, the Molecular Virology Research Group at Pompeu Fabra University (UPF), in collaboration with the Epitranscriptomics and RNA Dynamics group of the Center for Genomic Regulation (CRG), used the chikungunya virus as a model because its genome multiplies at extremely high levels.

“Our findings show for the first time that viruses modify the host tRNA to adapt the host translation machinery to the text of the viral mRNA,” says UPF’s Marc Talló. “In other words, the viral infection induces a change of language in the cell, so that it expresses the viral proteins very efficiently. As viral proteins are essential for the production of viruses, ultimately this change will be responsible for generating high numbers of viruses in the infected cell.”

Juana Díez, a full professor with the UPF Department of Medicine and Life Sciences and lead author of the study, says that even though the study focused on the chikungunya virus, the team hypothesizes that the modification of tRNAs induced by viral infection is a general mechanism followed by many viruses. “In addition, our results provide a basis for considering tRNA regulation as a new and promising therapeutic target for the development of broad-spectrum antivirals that are effective against multiple viruses,” Díez says.