Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 17, 2025 2 days, 5 minutes ago
Medical News: A new breakthrough study by Japanese scientists has uncovered a hidden mechanism that might be silently contributing to the ongoing mutation of the SARS-CoV-2 virus inside infected individuals. The study, conducted by researchers from Chiba University and Kobe University in Japan, reveals how a common type of RNA damage—caused by oxidative stress during infection—can interfere with the replication machinery of the virus, leading to potential genetic changes.
Oxidative RNA Damage in COVID-19 May Be Driving Dangerous Viral Mutations
This
Medical News report explores how the study sheds light on a specific type of RNA lesion known as 8-oxo-rG, which could be responsible for the frequent G to U mutations seen in the virus’s genetic code.
Understanding the Mutation Mechanism in SARS-CoV-2
Viruses like SARS-CoV-2, which carry their genetic information in single-stranded RNA, mutate rapidly. These mutations are part of the reason why new variants constantly emerge. While many of these mutations are random, some are triggered by the host’s own immune system, especially when cells respond to infection by producing reactive oxygen species (ROS). These molecules damage various cellular components, including RNA, and create lesions like 7,8-dihydro-8-oxoriboguanosine (8-oxo-rG) in the viral genome.
The researchers focused on how SARS-CoV-2’s RNA-dependent RNA polymerase (RdRp), the enzyme that replicates the viral genome, responds when it encounters these lesions. Using purified RdRp and synthetic RNA in a laboratory setup, the scientists demonstrated that replication was significantly slowed when the enzyme reached an 8-oxo-rG site. The replication either stalled or led to faulty copying of the genetic material.
Why This Type of Damage Is So Problematic
What makes 8-oxo-rG particularly dangerous is that it can mislead the viral RdRp enzyme into incorporating the wrong building blocks during replication. Normally, the enzyme would add rCMP (cytosine) opposite a regular rG (guanine) in the RNA strand. But when 8-oxo-rG is present, the polymerase sometimes adds rAMP (adenine) instead. This mismatch is a potential source of mutation, leading to G to U (or G to T in DNA terms) mutations when the virus replicates inside the host’s cells.
The study found that once RdRp manages to add a mismatched adenine (rAMP) across from 8-oxo-rG, it continues replication more easily than if it had added the correct match. This “preference” increases the risk that the mutation will be preserved and passed on as the virus multiplies.
Oxidation and the Mutation Explosion
During COVID-19 infection, the immune system’s response triggers high levels of inflammation and oxidative stress. This increases the production of ROS, which then damages not only the host cells but also the virus’s RNA. The lesion 8-oxo-rG, a hallmark of oxidative damage, becomes more common in these conditions.
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Because RNA viruses like SARS-CoV-2 rely solely on their RdRp for genome replication—and lack many repair mechanisms found in human cells—such lesions are not corrected. The study revealed that bypassing the lesion during replication is inefficient and often error-prone. Specifically, the enzyme prefers to keep going after inserting adenine rather than cytosine, resulting in a sevenfold higher error rate when the mismatch occurs.
Detailed Observations from the Study
Here are key experimental findings from the study:
-When encountering 8-oxo-rG, the viral RdRp often stalls, indicating that the lesion is a significant barrier to replication.
-Under these stalling conditions, the turnover rate of RdRp dropped significantly—from 4.9 × 10⁻³/min to 2.4 × 10⁻³/min.
-In terms of nucleotide incorporation, rCMP was still the preferred match to 8-oxo-rG, but rAMP was also inserted at a substantial rate—an error that increases the risk of mutation.
-The enzyme extended the RNA strand much more efficiently after inserting rAMP opposite the lesion than it did after inserting rCMP—despite the latter being the correct match.
-The bypass frequency for the rA:8-oxo-rG pair was seven times greater than that of the rC:8-oxo-rG, confirming that the mutation-prone pathway is favored.
Why It Matters for COVID 19 and Other RNA Viruses
The implications are profound. The findings suggest that viral mutations may not be solely the result of random errors or immune pressure but can also be driven by oxidative stress in the host. These mutations may not only help the virus survive hostile environments inside the body but also fuel the emergence of new variants with increased transmissibility, immune escape abilities, or resistance to treatments.
Interestingly, the SARS-CoV-2 RdRp has similar structural and functional characteristics as the polymerases in other RNA viruses like hepatitis C and influenza. This means the mechanism described in the study may apply broadly across RNA viruses, not just SARS-CoV-2.
Moreover, the researchers suggest that the interactions of RdRp with other viral and host proteins could influence how effectively the virus bypasses such lesions, adding another layer of complexity to the mutation process.
Could Targeting Oxidative Damage Be a Future Treatment Strategy
While the study doesn’t directly explore treatment options, it opens the door to new strategies that involve managing oxidative stress in COVID-19 patients.
Antioxidant therapies or drugs that modulate the activity of RdRp under oxidative conditions could potentially reduce the rate of harmful mutations.
However, caution is advised. Some previous studies suggest that ROS can also promote viral replication, so completely suppressing oxidative stress might backfire. A delicate balance must be maintained, and more research is needed to explore safe therapeutic options.
Conclusion
This study highlights how the body's own immune reaction to SARS-CoV-2—specifically the oxidative stress caused by ROS—can ironically contribute to the virus's evolution and survival. By damaging the viral RNA and allowing the virus’s replication enzyme to introduce errors, this process helps generate the mutations that give rise to new variants. Understanding these hidden pathways of mutation is crucial not only for understanding how SARS-CoV-2 evolves but also for developing targeted strategies to prevent the emergence of dangerous new strains. This underscores the importance of managing inflammation and oxidative stress during viral infections, not just to protect the host but to slow down viral mutation.
The study findings were published in the peer reviewed Journal of Biological Chemistry
https://www.sciencedirect.com/science/article/pii/S0021925825003618
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