When a virus infects a cell, it does more than just hijack the machinery to make new virus particles. It can also subtly reshape how the cell regulates its own RNA. Researchers from the Center for Medical Bioinformatics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP) explored this idea by looking at how SARS-CoV-2 infection changes chemical modifications on a special class of RNA molecules in human lung cells.

One of the most common chemical marks on RNA is N6-methyladenosine, usually shortened to m6A. This small modification can have big effects, influencing how long an RNA molecule survives in the cell and how well it carries out its role. m6A has been widely studied on messenger RNAs, which code for proteins, especially during viral infections. Much less is known about how m6A affects long noncoding RNAs, or lncRNAs, which do not make proteins but play important regulatory roles.

The researchers focused on human lung epithelial cells called Calu-3 cells, a widely used model for studying respiratory viruses. They analyzed direct RNA sequencing data, which allows scientists to read RNA molecules directly rather than converting them into DNA first. By combining this approach with machine learning tools designed to detect m6A marks, the team could map where methylation changes occurred after SARS-CoV-2 infection.

Their analysis revealed a broad increase in m6A levels across ten lncRNAs associated with antiviral responses. Three lncRNAs stood out in particular, UCA1, GAS5, and NORAD. These molecules are known to influence interferon signaling, a central pathway the body uses to detect viruses and activate immune defenses. Interferons help warn neighboring cells and limit viral spread, so changes in how interferon-related lncRNAs function can have significant consequences.

Interestingly, SARS-CoV-2 infection is often linked to a weakened or delayed interferon response. The increased m6A modification observed on these key lncRNAs may help explain why. By altering the stability, structure, or interactions of these RNAs, the virus could dampen interferon signaling and create a more favorable environment for its own replication.

The study also identified m6A marks within specific sequence patterns known as DRACH motifs, located in regions of lncRNAs predicted to form double-stranded structures. Methylation in these regions may destabilize local RNA structures or change how the RNA pairs with itself or binds to proteins. Such structural changes can influence which cellular partners the lncRNA interacts with, and how effectively it performs its regulatory functions.

Taken together, these findings highlight an additional layer of host manipulation by SARS-CoV-2. Beyond changing gene expression at the protein level, the virus appears to reshape the chemical landscape of regulatory RNAs that help control immune responses. Understanding these mechanisms could provide new insights into viral persistence and suggest future targets for antiviral strategies that focus on RNA regulation rather than viral proteins alone.