SARS-CoV-2’s spike protein causes host’s cellular shift from aerobic to anaerobic energy production via LDHB enzyme inhibition

COVID-19 News: The Viral Metabolism Hijack
The global SARS-CoV-2 pandemic, which has claimed millions of lives worldwide, has driven an urgent need for in-depth research into the virus's molecular mechanisms. While much of the focus has been on the virus's Spike glycoprotein and its role in binding to ACE2 receptors to facilitate viral entry into host cells, recent research reveals that the Spike protein may have a broader and more insidious role.


SARS-CoV-2’s spike protein causes host’s cellular shift from aerobic to anaerobic
energy production via LDHB enzyme inhibition

A study conducted by researchers from the University of Naples Federico II, CEINGE Biotecnologie Avanzate "Franco Salvatore," and Sapienza Università di Roma, Italy, that is covered in this COVID-19 News report, delves into the Spike protein’s unexpected influence on host cell metabolism. The findings suggest that the Spike protein can inhibit lactate dehydrogenase B (LDHB), a key enzyme in cellular metabolism, thereby triggering a shift from aerobic to anaerobic energy production, which could contribute significantly to the pathophysiology of COVID-19.
 
Unraveling the SARS-CoV-2 Spike Protein
SARS-CoV-2, the virus responsible for COVID-19, is a single-stranded RNA virus with a genome encoding 29 proteins, including four structural proteins: Spike (S), Membrane (M), Envelope (E), and Nucleocapsid (N). Once inside a host cell, the virus commandeers the cell's machinery to promote its survival and replication. A well-documented effect of viral infection, particularly in the case of RNA viruses like SARS-CoV-2, is metabolic reprogramming. This metabolic shift supports the biosynthesis of new viral particles by increasing glycolysis and other processes essential for viral replication.
 
In COVID-19, the link between altered metabolism and disease severity is evident. Elevated glucose levels in severe COVID-19 cases and the higher risk of severe disease in individuals with pre-existing metabolic disorders, such as diabetes, underscore the importance of metabolic pathways in the disease's progression. A prominent feature of this altered metabolism is the "Warburg Effect," a phenomenon where cells prefer glycolysis over oxidative phosphorylation, even in the presence of oxygen. This effect, often seen in cancer cells, has also been observed in cells infected by various viruses, including SARS-CoV-2.
 
The Spike Protein’s Role Beyond Viral Entry
The Spike glycoprotein of SARS-CoV-2 is primarily known for its role in viral entry, where it interacts with ACE2 and other receptors on the host cell surface. However, emerging evidence suggests that the Spike protein may have additional roles during the viral lifecycle. Research has shown that Spike can mediate the release of pro-inflammatory cytokines, influence leukocyte adhesion, and cause endothelial cell barrier dysfunction and injury. Furthermore, studies have indicated that the Spik e protein can impair mitochondrial functions in lung and brain endothelial cells, leading to disrupted cellular energy production and increased oxidative stress.
 
Interaction Between Spike Protein and LDHB: A New Discovery
In this study, researchers explored the interaction between the SARS-CoV-2 Spike protein and lactate dehydrogenase B (LDHB), an enzyme that plays a crucial role in the conversion of pyruvate to lactate in the cell's metabolic processes. Using an affinity purification mass spectrometry-based approach (AP-MS) in HEK-293T and Calu-3 cell lines, they identified LDHB as a protein partner of the Spike protein's S1 domain. This interaction was further confirmed through co-immunoprecipitation and immunofluorescence, which showed colocalization of LDHB and the S1 domain in cells.
 
The inhibition of LDHB by the Spike protein leads to an increase in lactate levels in cells expressing the Spike S1 subunit. This finding suggests that the Spike protein may be causing a metabolic shift from aerobic to anaerobic energy production by depriving LDHB of NAD+, a critical cofactor for its enzymatic activity. The study pinpointed the region of the Spike protein that interacts with NAD+, primarily involving the W436 residue within the receptor-binding domain (RBD).
 
Implications of the Metabolic Shift
The discovery that the SARS-CoV-2 Spike protein can inhibit LDHB and induce a metabolic shift has significant implications for understanding the virus's pathophysiology. The Warburg Effect, characterized by increased glycolysis and lactate production, is commonly seen in viral infections and cancer. By promoting this effect, SARS-CoV-2 may create a cellular environment that favors its replication and spread.
 
This metabolic reprogramming could also explain some of the severe symptoms observed in COVID-19 patients, such as hypoxia and multi-organ failure. The shift to anaerobic metabolism, coupled with impaired mitochondrial function, can lead to decreased ATP production and increased oxidative stress, contributing to cell damage and the exacerbation of symptoms.
 
Broader Implications for Viral Infections
The findings from this study are not only relevant to SARS-CoV-2 but also to our understanding of how other viruses manipulate host cell metabolism. The inhibition of LDHB and the subsequent metabolic shift could be a common strategy employed by various pathogens to create a more favorable environment for their survival and replication. This research opens up new avenues for exploring how metabolic pathways can be targeted to develop therapeutic strategies against viral infections.
 
Conclusion: A New Frontier in COVID-19 Research
The discovery that the SARS-CoV-2 Spike protein can manipulate host cell metabolism by inhibiting LDHB represents a significant advancement in our understanding of the virus's impact on the host. This novel mechanism, involving the interaction between Spike and NAD+ to inhibit LDHB, could explain some of the metabolic alterations observed in COVID-19 patients and offer new targets for therapeutic intervention.
 
As the world continues to grapple with the COVID-19 pandemic, research such as this is crucial for developing strategies to combat the virus and prevent future outbreaks. Further studies are needed to explore the full extent of the Spike protein's effects on cellular metabolism and to determine how these findings can be translated into effective treatments.
 
The study findings were published in the peer reviewed International Journal of Biological Macromolecules.
https://www.sciencedirect.com/science/article/abs/pii/S0141813024054436
 
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https://www.thailandmedical.news/news/sars-cov-2-spike-proteins-causes-mitochondrial-dysfunction-and-exhibits-warburg-effect,-leading-to-redox-shift-and-cellular-anabolism
 
https://www.thailandmedical.news/news/covid-19-research-longitudinal-analysis-of-pbmc-proteomics-reveals-metabolic-alterations-in-covid-19
 
https://www.thailandmedical.news/news/philadelphia-study-validates-that-sars-cov-2-causes-mitochondrial-metabolic-and-epigenomic-reprogramming