SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE
Charles N. S. Allen,
Maryline Santerre,
Sterling P. Arjona,
Lea J. Ghaleb,
Muna Herzi,
Megan D. Llewellyn,
Natalia Shcherbik,
Bassel E. Sawaya
Affiliations
Charles N. S. Allen
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Maryline Santerre
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Sterling P. Arjona
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Lea J. Ghaleb
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Muna Herzi
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Megan D. Llewellyn
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Natalia Shcherbik
Department for Cell Biology and Neuroscience, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
Bassel E. Sawaya
Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.
