SARS-CoV-2 Variant Mutation in NSP6 Weakens Immune Defenses and Hijacks Host Cell Signaling
Nikhil Prasad Fact checked by:Thailand Medical News Team May 15, 2025 16 hours, 42 minutes ago
Medical News: How a Tiny Viral Mutation Could Make COVID-19 Variants More Dangerous
Scientists from Zhengzhou University and Hainan Medical University in China have uncovered how tiny genetic changes in the SARS-CoV-2 virus—specifically in one of its nonstructural proteins called NSP6—can significantly impact how the virus behaves inside human cells. These changes can help the virus evade the immune system and hijack the host’s own molecular machinery to reproduce and spread, potentially increasing the severity of infections and weakening the body’s defenses.
SARS-CoV-2 Variant Mutation in NSP6 Weakens Immune Defenses and Hijacks Host Cell Signaling
This
Medical News report details the team’s focus on NSP6, a critical protein in SARS-CoV-2 known for helping the virus replicate and escape detection by the body’s immune system. The researchers analyzed mutations in the NSP6 gene from multiple dominant variants of the virus, including Alpha, BA.2.86, XBB.1.16, and JN.1. They discovered how these mutations not only altered the structure and stability of the protein but also disrupted crucial immune signaling and cellular responses—an alarming insight with potential implications for future waves of COVID-19.
Why NSP6 Matters in COVID-19 Evolution
NSP6 is a membrane-bound protein that helps the virus build its replication compartments inside infected cells. It also influences inflammation and immune responses. In this study, researchers looked at several mutations found in variants like JN.1 (V3593F, R3821K), BA.2.86 (V3593F), and XBB.1.16 (L3829F). These mutations, especially when combined with a commonly deleted segment known as ∆SGF, caused structural changes in NSP6 that affected how it interacted with host cell machinery.
Structural modeling showed that the V3593F mutation disrupted hydrogen bonding, R3821K exposed buried amino acids to the protein surface (potentially changing how NSP6 binds to other molecules), and L3829F increased protein flexibility. These structural changes made the mutated protein less stable and more capable of interfering with the host’s natural defense systems.
Turning Off the Immune System’s Alarm
To better understand how NSP6 affects the immune system, the team inserted the various mutant NSP6 genes into human lung cells and examined the resulting changes. Normally, when the body detects viruses, it activates a powerful immune signaling pathway known as type I interferon signaling, which includes molecules like IFN-α, IFN-β, and key proteins like p-IRF3 and p-STAT1 that help ramp up the body’s antiviral defenses.
However, in cells expressing wild-type NSP6, these immune factors were suppressed. The Alpha, BA.2.86, and JN.1 versions of NSP6 also significantly blocked this response, but XBB.1.16 showed a reduced ability to do so. This difference may help explain why certain variants are more successful at hiding from the immune system, giving them a dangerous edge in spreading
through populations.
Hijacking the Host Cell’s Growth Machinery
Beyond immune evasion, the study showed that these mutated versions of NSP6 could also influence a critical pathway inside cells called the p53-AKT-mTOR signaling pathway. This pathway regulates how cells grow, divide, and respond to stress. When infected with SARS-CoV-2 carrying certain NSP6 mutations, the p-AKT and p-mTOR proteins were abnormally activated—essentially rewiring the cell’s internal machinery to favor viral replication.
Interestingly, the researchers also tested what would happen if they blocked a protein called p53, which normally acts as a guardian against harmful changes inside cells. When p53 was inhibited, cells expressing Alpha or BA.2.86 NSP6 showed even more mTOR activation, indicating that these viral proteins manipulate multiple systems to ensure the virus thrives.
Implications for COVID-19 Therapies and Future Research
This study offers crucial insights into how tiny mutations in SARS-CoV-2 can have outsized effects on disease severity and immune evasion. It highlights NSP6 as a potential target for future antiviral treatments or vaccine strategies. Drugs that can block NSP6's interference with immune signaling or its manipulation of host pathways may offer a new layer of defense against current and future variants.
Conclusions
The research clearly shows that mutations in the SARS-CoV-2 NSP6 protein significantly impact the virus's ability to hide from the immune system and alter key cell signaling pathways. These changes weaken the body’s early defenses and enhance viral replication by hijacking the p53-AKT-mTOR pathway. The findings emphasize the need to closely monitor even minor genetic changes in the virus, as they can lead to major shifts in how the virus spreads and causes disease. Understanding these mechanisms will be crucial in developing more effective treatments and preparing for new waves of COVID-19.
The study findings were published in the peer reviewed journal: Current Issues in Molecular Biology.
https://www.mdpi.com/1467-3045/47/5/361
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