A new study describes how the functioning of RNA changes in cells infected by SARS-CoV-2, the COVID-19 virus. The findings provide clues as to how different variants can escape the immune system, and serve as a basis for the development of novel treatments.

For the first time, scientists have shown that infection by SARS-CoV-2, the virus that causes COVID-19, changes the functioning of host cell RNA. The researchers, from the Federal University of São Paulo (UNIFESP) in Brazil, arrived at this conclusion by analyzing 13 datasets obtained during four studies of viral, human, and animal cell RNA.

The most recent study, reported in an article published in the journal Frontiers in Cellular and Infection Microbiology, examined the epitranscriptome of Vero cells (derived from monkeys) and human Calu-3 cells by direct RNA sequencing. An epitranscriptome is the collection of biochemical modifications of cell RNA, such as methylation.

“Our first important finding in this study was that infection by SARS-CoV-2 increases the level of m6a [N6-methyladenosine], a type of methylation, in host cells compared with non-infected cells,” Marcelo Briones, last author of the article, told Agência FAPESP. Briones is a professor at UNIFESP’s Medical School (EPM) and a researcher affiliated with its Center for Medical Bioinformatics.

Methylation is a biochemical modification involving the addition of a methyl group to a substrate. It occurs in cells via the action of enzymes capable of transferring part of one molecule to another. This changes the behavior of proteins, enzymes, hormones, and genes. The researchers demonstrated changes to infected cell RNA quantitatively by analyzing all the RNAs present in the cells and qualitatively by locating on a map the number of methylations per region in the nucleotides.

The study was a continuation of an earlier genomic analysis published in 2021, where the researchers analyzed the methylation pattern in SARS-CoV-2.

“Methylation has two functions in viruses. It regulates protein expression, and it defends the virus against the action of interferon, a potent antiviral substance produced by the host organism,” Briones said.

In both studies, the researchers analyzed m6a because it is the most common type of RNA nucleotide modification and is involved in several significant processes, such as intracellular location and protein translation. RNA nucleotides contain nitrogenous bases (adenine, guanine, uracil, or cytosine) running along a single strand. The team also discovered that different strains of the virus displayed variations in the sequences of nitrogenous bases in their nucleotides. “Some strains may be much more methylated than others. If so, they can proliferate better inside host cells,” Briones said.

They also found that nucleotide sequences known as m6a DRACH motifs were slightly different in SARS-CoV-2 and in cells. In this acronym, which is frequently used in epigenetics, the letter D stands for adenine, guanine, or uracil; R for adenine or guanine; A for the methylated residue; C for cytosine; and H for adenine, cytosine or uracil.

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