SARS-CoV-2 Spike Protein Interacts with 12 Liver Proteins, Reactivates HBV and Activates Pre-Cancerous Pathways!

Medical News: Recent research has uncovered alarming interactions between the SARS-CoV-2 Spike (S) protein and the human liver, revealing its potential role in reactivating hepatitis B virus (HBV) and initiating pre-cancerous molecular pathways. This groundbreaking study, conducted by Giovanni Colonna from the Medical Informatics Unit at the University of Campania in Naples, Italy, has shed light on how the Spike protein’s unique ability to bind directly to liver proteins could have far-reaching implications for individuals recovering from COVID-19 or vaccinated against it.


SARS-CoV-2 Spike Protein Interacts with 12 Liver Proteins, Reactivates HBV
and Activates Pre-Cancerous Pathways

The Hidden Interactions of the S-Protein
SARS-CoV-2’s spike protein, specifically the S1 subunit, is widely known for enabling the virus to bind to the ACE2 receptor and infect human cells. However, this study which is covered in this Medical News report, took a closer look at the autonomous activity of the S1 subunit within the human body. The research revealed that the S1 protein can persist for extended periods and interact directly with various human proteins, even after the virus has been cleared or following vaccination. Among the 626 human proteins that the S1 protein can bind to, 12 were found to interact specifically within the liver. These proteins include ACE2, AGER, DPP4, ESR1, TLR4, and others.
 
Through advanced techniques such as protein-protein interaction mapping via BioGRID and STRING databases, researchers identified how these liver proteins serve as key hubs in molecular pathways that contribute to the progression of liver diseases. Importantly, these pathways appear to play a dual role in both exacerbating existing liver conditions and potentially initiating new ones, such as hepatocellular carcinoma (HCC).
 
Reactivation of HBV and Shared Pathways
The study’s findings demonstrate that the SARS-CoV-2 S1 subunit reactivates HBV in certain conditions, particularly in individuals with compromised immune systems or pre-existing HBV infections. Reports of HBV reactivation in COVID-19 patients have been documented globally, raising concerns about the long-term implications of SARS-CoV-2 on liver health. This reactivation is driven by the overlap in molecular pathways shared by SARS-CoV-2 and HBV.
 
Notably, pathways involving the JAK/STAT signaling cascade - a critical regulator of immune responses and cell proliferation - are activated by the S1 protein in liver cells. These pathways are also pivotal in HBV replication and persistence, suggesting a molecular synergy that favors HBV reactivation. Additionally, the PI3K-AKT signaling pathway, often implicated in cancer development, was enriched in the liver cells studied, highlighting the potential for these molecular interactions to drive pre-cancerous conditions.
 
Pre-Cancerous Pathways Uncovered
The study revealed alarming evidence that SARS-CoV-2’s S1 protein activates several molecul ar mechanisms that can contribute to liver cancer development. Key genes involved in tumor suppression, such as TP53, were found to be dysregulated. Oncogenes like CTNNB1 and EGFR, which promote cell proliferation and survival, were also activated.
 
Analysis of the molecular pathways indicated that the S1 protein induces changes in cellular processes such as apoptosis (programmed cell death), autophagy (cellular recycling), and inflammation. These processes, while normally protective, can be hijacked to favor cancerous growth under specific conditions. For instance, prolonged inflammation - a hallmark of chronic HBV infection - can create an environment that promotes DNA damage and genetic mutations, setting the stage for liver cancer.
 
Quantitative Findings
The study identified a network of 676 proteins linked to the liver, with 12 directly interacting with the S1 protein. Among these, the researchers observed significant activation of pathways associated with hepatocellular carcinoma (HCC) and HBV. Specifically:
 
-HCC Pathways: 54 out of 161 network genes were directly implicated in HCC-related processes, with a statistical significance (FDR) of 1.38 × 10⁻³¹.
 
-HBV Pathways: 90 out of 158 network genes were linked to HBV-related processes, with an FDR of 2.37 × 10⁻⁶⁷.
 
-Overlap: 31 genes were shared between HBV and HCC pathways, underscoring the interconnected nature of these processes.
 
The data also highlighted the role of protein hubs like PRKACB, which interacts with over 120 other proteins, acting as a key regulator in liver cell signaling. This protein’s involvement in cell cycle regulation, microtubule dynamics, and chromatin remodeling further underscores its significance in liver disease progression.
 
Individual Variability and Epigenetic Factors
The study emphasized the role of individual variability in determining the outcomes of these molecular interactions. Factors such as pre-existing liver conditions, genetic predispositions, and environmental influences were found to significantly modulate the impact of the S1 protein on liver health.
 
Epigenetic modifications - changes in gene expression that do not alter the DNA sequence - were identified as a major factor. Key genes, including TP53, BAX, FOXO1, and AKT1, were found to undergo epigenetic changes that could either exacerbate or mitigate disease progression. For instance, methylation of the TP53 gene was linked to impaired tumor suppression, while acetylation of FOXO1 was associated with increased cancer risk.
 
Broader Implications for Liver Health
The implications of these findings extend beyond COVID-19 and vaccination. The study suggests that SARS-CoV-2’s impact on liver proteins could exacerbate other liver conditions, including non-alcoholic fatty liver disease (NAFLD) and alcohol-induced liver damage. By activating pathways linked to inflammation and fibrosis, the S1 protein could accelerate the progression of these conditions in susceptible individuals.
 
Additionally, the study highlights the potential for SARS-CoV-2 to disrupt liver metabolism. The liver’s role in detoxification and energy production makes it particularly vulnerable to disruptions in cellular signaling pathways. Prolonged interference by the S1 protein could lead to systemic effects, including metabolic imbalances and heightened vulnerability to other diseases.
 
Personalized Approaches to Treatment
One of the most promising aspects of this research is its potential application in personalized medicine. By using the identified protein interactions as a molecular “toolkit,” clinicians can develop diagnostic and therapeutic strategies tailored to individual patients. For example, monitoring the activity of specific genes and pathways linked to HBV and HCC could help identify high-risk patients early, allowing for timely interventions.
 
Limitations and Future Directions
While the study provides valuable insights, it acknowledges the limitations of using model cell systems and in vitro data. The absence of direct patient-derived data underscores the need for clinical studies to validate these findings. Future research should focus on longitudinal studies involving COVID-19 survivors and vaccinated individuals to assess the long-term impact of the S1 protein on liver health.
 
Further exploration of the molecular mechanisms underlying these interactions could also lead to the development of targeted therapies. For instance, inhibitors of the PI3K-AKT and JAK/STAT pathways could potentially mitigate the adverse effects of the S1 protein on the liver.
 
Conclusion
In summary, the findings of this study underscore the complex and far-reaching effects of the SARS-CoV-2 S1 protein on liver health. By interacting with 12 specific liver proteins, the S1 protein not only reactivates HBV but also activates pathways that could lead to liver cancer. These interactions are influenced by individual factors such as genetics, metabolism, and epigenetics, highlighting the need for personalized approaches to diagnosis and treatment.
 
The study’s insights into the molecular mechanisms of SARS-CoV-2’s impact on the liver provide a critical foundation for future research and clinical practice. As the world continues to grapple with the long-term effects of COVID-19, understanding these interactions will be essential for mitigating their impact on global health.
 
The study findings were published in the peer-reviewed journal Livers.
https://www.mdpi.com/2673-4389/5/1/1
 
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