Nikhil Prasad Fact checked by:Thailand Medical News Team Oct 06, 2025 2 hours, 1 minute ago
Medical News: Scientists Warn of Dangerous Mutations in a Neglected Viral Protein
As new SARS-CoV-2 lineages continue to emerge across the world, researchers are now turning their attention to one of the virus’s lesser-known but highly dangerous components—the ORF3a accessory protein. Unlike the much-discussed spike protein mutations that help the virus evade immunity, ORF3a mutations may be directly linked to how severely the virus damages human cells and organs.
One of the latest lineage to have emerged, XFG.3.4.1 + Orf3a:A72T, features a mutation in this critical gene.
https://github.com/sars-cov-2-variants/lineage-proposals/issues/2986
According to scientists studying viral evolution, such mutations could alter how the virus manipulates host cells, potentially leading to higher inflammation, greater tissue injury, and an overall increase in pathogenicity. This
Medical News report highlights growing concerns that SARS-CoV-2 may be quietly evolving new tools for cell destruction hidden within its accessory proteins rather than its spike gene.
ORF3a’s Dark Role in Triggering Cell Death and Inflammation
The ORF3a protein functions as a viroporin—essentially a channel-forming protein that disrupts host cell membranes. It has been shown to activate apoptosis (programmed cell death) and pyroptosis (a highly inflammatory form of cell death), both of which contribute to the extensive lung and organ damage seen in severe COVID-19 cases.
Research published in Frontiers in Microbiology found that ORF3a interacts with host inflammasome pathways, leading to the uncontrolled release of inflammatory cytokines.
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.854567/full
When expressed in human lung cells, ORF3a induces caspase-dependent cell death, inflammation, and cellular stress—mechanisms that collectively worsen respiratory failure and multi-organ inflammation.
What makes this even more alarming is that ORF3a’s destructive capabilities can manifest even when viral loads are relatively low, meaning patients could experience severe inflammation disproportionate to the amount of virus in their bodies.
The Threat of the A72T Mutation
The newly observed A72T mutation in the XFG.3.4.1 lineage occurs in a structurally important region of the protein that influences how ORF3a folds and forms ion channels. Any alteration here could change how the protein interacts with host membranes and immune pathways. The result could be faster cell death, stronger inflammatory responses, and potentially more severe disease outcomes.
If future SARS-CoV-2 lineages accumulate similar ORF3a mutations, the world could face new viral strains that are not necessarily more contagious but significantly more damaging to human health.
Scientists are urging that global genomic surveillance expand beyond spike mutations to include ORF3a and other accessory proteins that might hold the true key to COVID-19’s evolving virulence.
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Read Also:
https://www.thailandmedical.news/news/scientists-from-maryland-discover-that-sars-cov-2-orf3a-protein-causes-brain-cell-death
https://www.thailandmedical.news/news/sars-cov-2-orf3a-protein-hijacks-clcc1-chloride-channel-to-cause-endoplasmic-reticulum-dysfunction
https://www.thailandmedical.news/news/sars-cov-2-s-orf3a-protein-manipulates-cholesterol-levels-in-the-host
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