SARS-CoV-2 Triggers Methylation Shifts in Long Non-Coding RNA to Suppress Immunity and Promote Viral Persistence
Nikhil Prasad Fact checked by:Thailand Medical News Team Jun 10, 2025 1 month, 2 weeks, 2 days, 48 minutes ago
Thailand Medical News: A New Mechanism in the Virus’s Arsenal
A new study by Brazilian researchers has uncovered an alarming mechanism used by SARS-CoV-2 to weaken human immune responses and extend its survival in the body. Scientists from the Center for Medical Bioinformatics and the Department of Microbiology, Immunology and Parasitology at the Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), have found that the virus manipulates chemical tags called methyl groups on long non-coding RNAs (lncRNAs) within human lung cells. These changes, involving N⁶-methyladenosine (m⁶A) modifications, are believed to silence key immune processes and allow the virus to persist.
SARS-CoV-2 Triggers Methylation Shifts in Long Non-Coding RNA to Suppress Immunity and Promote Viral Persistence
This
Thailand Medical News report is based on a detailed analysis using direct RNA sequencing (dRNA-seq) and machine learning tools to map methylation changes. The researchers observed that infection with SARS-CoV-2 caused broad shifts in the m⁶A landscape of lncRNAs—molecules that don’t code for proteins but are vital for regulating genes, including those responsible for immune defenses.
Disrupting the Host’s Molecular Defenses
Among the 100 lncRNAs analyzed, ten showed the most significant changes in methylation during infection. Notably, lncRNAs like GAS5, NORAD, and UCA1, which are involved in interferon signaling (a critical antiviral response), displayed significant increases in m⁶A modifications. GAS5 and NORAD were both upregulated and hypermethylated, potentially reducing their ability to suppress harmful inflammation and allowing viral replication to continue unchecked. Meanwhile, UCA1 showed a unique pattern—it was downregulated in terms of expression but gained m⁶A tags, which may prevent it from regulating immune-suppressive pathways properly.
The study uncovered that many of these chemical changes occur in specific RNA regions called DRACH motifs. These are sequence patterns where the m⁶A methylation is most likely to occur. The addition of methyl groups in these motifs, especially within or near interaction zones of the RNA, appears to destabilize their structure. This prevents them from forming the necessary RNA-RNA or RNA-protein interactions that trigger immune signaling.
Unraveling Viral Tricks to Avoid Detection
Interestingly, m⁶A modifications were found to interfere with how lncRNAs normally “sponge” microRNAs—short RNAs that regulate gene expression. For instance, the UCA1 molecule typically sequesters miR-145, which controls the expression of SOCS7, a known interferon suppressor. When UCA1 is methylated, it loses this ability, possibly lifting restrictions on SOCS7 and weakening immune reactions further.
The study also found direct interaction between UCA1 and the SARS-CoV-2 genome, suggesting that the virus may exploit certain RNA regions to prevent proper methylation or use them to
hide from the immune system altogether.
Fine-Tuning the Immune System for Viral Gain
The findings highlight that m⁶A methylation is not random but appears to be selectively guided by the virus. Changes in the surrounding RNA sequences near DRACH motifs suggest that the viral infection reprograms the methylation machinery of the host cell. This fine-tuning ensures that the host’s immune response is muted just enough to avoid early detection while allowing the virus to replicate and persist.
A Warning from the Lab
The researchers propose that m⁶A modifications might switch the way RNA strands pair—disrupting normal A-U base pairings and allowing temporary, unstable formations called Hoogsteen base pairs. This may reduce the ability of lncRNAs to bind with target molecules, further hindering immune signaling.
In addition to weakening the interferon (IFN) response, the study found that while IFN-β was slightly induced, other critical interferons like IFN-α and IFN-γ were completely absent in infected cells. This supports the idea that SARS-CoV-2 uses these epitranscriptomic changes to blunt one of the body’s most powerful antiviral defenses.
Conclusion
This research presents compelling evidence that SARS-CoV-2 manipulates RNA methylation on long non-coding RNAs to disrupt immune responses at the molecular level. By remodeling m⁶A tags in a targeted and strategic way, the virus weakens host defenses, destabilizes RNA structures involved in immune regulation, and hijacks cell functions to ensure its survival. The discovery not only sheds light on a previously unknown viral evasion strategy but also opens up new pathways for potential treatments that could block or reverse these RNA modifications. Targeting the m⁶A machinery may prove to be a powerful therapeutic strategy to bolster host immunity and combat long-term viral persistence.
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2025.06.08.658496v1
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