Study Shockingly Finds That SARS-CoV-2 Non-Spike Proteins Can Cause Changes to Mucosal Epithelial Cells and Impact Health

Medical News: Scientists Uncover How SARS-CoV-2 Non-spike Proteins Affect Human Cells
A recent study has uncovered alarming new details about how SARS-CoV-2, the virus responsible for COVID-19, manipulates human cells. Unlike previous research that primarily focused on the virus’s spike protein, this study highlights the role of non-spike structural proteins in hijacking mucosal epithelial cells.


Study Shockingly Finds That SARS-CoV-2 Non-Spike Proteins Can Cause Changes to Mucosal Epithelial
Cells and Impact Health

Researchers from institutions such as the University of Plymouth in the United Kingdom, the State University of Campinas in Brazil, the National Institute of Environmental Health Sciences in the United States, and Nanjing Medical University in China contributed to this groundbreaking work.
 
Understanding Mucosal Epithelial Cells and Their Role in Protection
Mucosal epithelial cells line various organs, including the lungs, oral cavity, and gastrointestinal tract, serving as the first barrier against infections. These cells maintain a delicate balance between differentiation and regeneration, ensuring proper tissue function and repair. However, when SARS-CoV-2 infects the human body, its non-spike structural proteins - including the envelope (E), membrane (M), and nucleocapsid (N) proteins - disrupt this balance, leading to severe cellular changes. This Medical News report explores the findings in detail, explaining how these viral proteins alter human cell function and why this matters for COVID 19 patients.
 
The Study Findings Reveal a New Mechanism of Cellular Damage
The research team discovered that SARS-CoV-2 infection triggers a process called epithelial cell dedifferentiation. In healthy tissues, cells maintain their specialized roles, but under viral influence, they revert to an immature state. This phenomenon was observed in tissue samples from COVID-19 patients, including the oral mucosa, lung, and kidney. The study revealed that the presence of SARS-CoV-2 significantly reduced the expression of differentiation markers such as Keratin 4 and E-cadherin while increasing the levels of Keratin 14, a marker of immature cells.
 
Further investigations using laboratory models confirmed that the E, M, and N proteins directly induce dedifferentiation in epithelial cells. The most striking effect was attributed to the E protein, which not only caused dedifferentiation but also disrupted normal cell cycle progression. Scientists observed that cells infected with SARS-CoV-2 structural proteins were arrested in the G1 phase, preventing them from dividing and leading to an accumulation of dysfunctional cells. This phenomenon is particularly concerning because it may contribute to tissue damage and delayed healing in COVID-19 patients.
 
Disrupting Epithelial Stratification and Wound Healing
In addition to dedifferentiation, the study found that the SARS-CoV-2 E protein severely impacts epithelial stratification, the process b y which cells organize into structured layers. This disruption was observed in three-dimensional human oral mucosa models, where exposure to the E protein resulted in disorganized tissue formation and an increase in apoptotic (dying) cells. Researchers noted a significant reduction in key structural proteins like Keratin 4 and E-cadherin, alongside an increase in Keratin 14, indicating impaired cellular maturation.
 
The study also demonstrated that COVID-19 patients often experience delayed wound healing, particularly in the oral cavity, throat, and gastrointestinal tract. This delay is likely due to the virus’s ability to interfere with epithelial regeneration, making it harder for damaged tissues to recover. The findings suggest that targeting the E protein could be a potential strategy for improving tissue repair in infected patients.
 
The Role of CNN2 and GLIS2 in Viral Hijacking
To understand the molecular mechanisms behind these cellular changes, researchers performed proteomic analysis to identify key proteins affected by SARS-CoV-2 non-spike structural proteins. Their findings pointed to Calponin-2 (CNN2), an actin associated protein involved in cellular structure and movement, as a major target of the viral proteins. CNN2 was found to be significantly upregulated in infected tissues, leading to increased apoptosis and tissue damage.
 
Additionally, the study identified GLIS2, a transcription factor known to regulate gene expression, as a critical player in this process. GLIS2 was downregulated in infected cells, leading to unchecked CNN2 activity. This imbalance contributes to cellular instability and further exacerbates tissue damage. Importantly, experiments showed that knocking down CNN2 could partially restore normal cell differentiation and reduce apoptosis, highlighting it as a potential therapeutic target.
 
Implications for COVID-19 Treatment and Recovery
The study’s findings offer critical insights into why COVID-19 patients experience severe tissue damage and slow recovery. By demonstrating that non-spike structural proteins, particularly the E protein, play a crucial role in epithelial dysfunction, researchers have identified new potential drug targets. Therapies aimed at inhibiting CNN2 expression or restoring GLIS2 activity could help mitigate the virus’s harmful effects on epithelial tissues.
 
Moreover, the discovery that SARS-CoV-2 disrupts epithelial stratification and wound healing underscores the need for targeted treatments to promote tissue regeneration in affected patients. Understanding how the virus manipulates epithelial cells provides a clearer picture of COVID-19 pathology and opens new avenues for intervention.
 
Conclusion
The revelation that SARS-CoV-2 non-spike structural proteins can induce epithelial dedifferentiation and disrupt cellular organization is a major breakthrough in understanding COVID-19. Unlike previous research that focused primarily on the spike protein’s role in viral entry, this study highlights how other viral components actively contribute to disease severity. The ability of the E protein to interfere with epithelial stratification and cell cycle progression suggests that it plays a more significant role in COVID-19 pathology than previously recognized.
 
The findings also emphasize the importance of CNN2 and GLIS2 as key molecular players in the virus’s ability to hijack human cells. Future research focusing on therapeutic interventions targeting these pathways could lead to improved treatments for COVID-19 patients, particularly those suffering from severe epithelial damage. As scientists continue to explore the long-term effects of SARS-CoV-2 infection, studies like this will be crucial in guiding medical strategies to combat the virus and its complications.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.researchsquare.com/article/rs-6073524/v1
 
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