Dietary alpha‐ketoglutarate inhibits SARS CoV‐2 infection and rescues inflamed lungs to restore O2 saturation by inhibiting pAkt

• Published in: Clinical and translational medicine 2022-09, Vol.12 (9), p.e1041-n/a
• Main Authors: Agarwal, Sakshi, Kaur, Simrandeep, Asuru, Tejeswara Rao, Joshi, Garima, Shrimali, Nishith M, Singh, Anamika, Singh, Oinam Ningthemmani, Srivastva, Puneet, Shrivastava, Tripti, Vrati, Sudhanshu, Surjit, Milan, Guchhait, Prasenjit
• Format: Article
• Language: English
• Subjects: Aging; Blood platelets; Coronaviruses; COVID-19; DNA methylation; Enzymes; Heart surgery; Infections; Inflammation; Investigations; Letter to the Editor; Lungs; Pathogenesis; Proteins; Severe acute respiratory syndrome coronavirus 2; Thrombosis; Viral infections
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1041

Unlike with other respiratory viral infections, symptoms of COVID-19 are very heterogeneous ranging from minimal to Acute Respiratory Distress Syndrome (ARDS).1 Elevated intravascular clots, accumulation of leukocytes including neutrophils and macrophages, deposition of collagen, mucus, and other extracellular matrix, and accumulation of fluid in alveoli lead to reduced blood-gas barrier permeability and exchange of O2, causing a condition called hypoxemia or decreased oxygen pressure saturation (SpO2) in COVID-19.2 With a focus on our investigation to inhibit viral infection and rescue lung pathogenesis in COVID-19, we tested the effect of alpha-ketoglutarate (αKG), a common metabolite of the Krebs cycle, in SARS CoV-2-infected animals. Recently, we reported that αKG, a co-factor of prolyl hydroxylase 2(PHD2), augmented the prolyl hydroxylation activity of the enzyme and significantly degraded its substrates such as phosphorylated-Akt (pAkt)3 and HIF1α / HIF2α.4 Dietary supplementation of αKG significantly reduced pro-inflammatory and pro-thrombotic responses of leukocytes and platelets in conjunction with downmodulation of pAkt in mice.3 Studies have reported the usage of αKG to improve human health. Administration of αKG in blood cardioplegia improved myocardial protection in patients with heart surgery.5 Dietary supplementation of αKG along with vitamin delayed human aging.6 It is now known that (1) SARS CoV-2 employs Akt signalling for propagation in its host7 and (2) pAkt promotes platelet activation and thrombosis as well as leukocyte activation and inflammation in SARS CoV-2-infected animals.3 We, therefore, investigated whether (1) αKG could inhibit SARS CoV-2 replication by downmodulating pAkt in vitro and in vivo, and (2) dietary supplementation of the metabolite could rescue the lung pathogenesis to restore normal O2 saturation in infected animals. SEE PDF] In conclusion, our study describes that αKG significantly inhibits SARS CoV-2 replication and reduces inflammation, thrombosis and apoptotic cell death in the lungs to restore normal SpO2 saturation in infected animals without affecting the anti-viral response of CD4 and CD8 T cells, and IgG. [...]our study strongly suggests a potential use of this metabolite as one of the first-line therapeutics for COVID-19.