Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19

Area of Science:

• Immunology
• Metabolic pathways
• Respiratory infections

Background:

• Anorexia and fasting trigger ketogenesis, producing beta-hydroxybutyrate (BHB).
• The role of ketogenesis in modulating immune responses during pulmonary infections is not fully understood.
• SARS-CoV-2 and influenza infections can lead to acute respiratory distress syndrome (ARDS).

Purpose of the Study:

• To investigate the impact of ketogenesis and BHB on immune responses in pulmonary viral infections.
• To determine if BHB production differs between SARS-CoV-2 and influenza-induced ARDS.
• To explore BHB's potential as a therapeutic agent in severe respiratory infections.

Main Methods:

• Comparative analysis of BHB production in patients with SARS-CoV-2-induced ARDS versus influenza-induced ARDS.
• Assessment of BHB's effects on CD4+ T cell survival, interferon-gamma production, and metabolism using metabolic tracing.
• In vivo studies using mice with severe respiratory infections, treated with ketogenic diets and BHB ketone ester drinks.

Main Results:

• BHB production is impaired in SARS-CoV-2 ARDS but not in influenza ARDS.
• BHB enhances CD4+ T cell survival and interferon-gamma production.
• BHB fuels T cell oxidative phosphorylation, supports amino acid and glutathione production, and restores function in SARS-CoV-2 ARDS T cells.
• Ketogenic diet and BHB supplementation reduce mortality in mice with severe respiratory infections.

Conclusions:

• BHB is a crucial alternative carbon source supporting T cell responses in pulmonary viral infections.
• Impaired ketogenesis and subsequent BHB deficiency may be a significant factor in the severity of COVID-19.
• BHB supplementation shows therapeutic potential for severe respiratory viral infections.