STING-mediated metabolic reprogramming drives lipid peroxidation during Staphylococcus aureus infection

Area of Science:

• Immunology
• Metabolic pathways
• Host-pathogen interactions

Background:

• Metabolism underpins physiological functions, with fatty acid metabolism critical for immune responses.
• The innate immune receptor STING (Stimulator of Interferon Genes) modulates metabolism during infection.

Purpose of the Study:

• To investigate the role of STING in host lipid metabolism during Staphylococcus aureus infection.
• To elucidate the mechanism by which STING reprograms cellular metabolism in response to pathogens.

Main Methods:

• Activation of STING in S. aureus-infected mammary epithelial cells.
• Analysis of lipid accumulation, lipid peroxide production, and glutathione (GSH) levels.
• Investigating the interaction between STING and fatty acid synthase (FASN), stearoyl-CoA desaturase 2 (SCD2), and acyl-CoA synthetase long-chain family member 4 (ACSL4).
• Utilizing genetic ablation and pharmacological inhibition of STING.

Main Results:

• STING activation in infected cells led to significant lipid accumulation, increased lipid peroxide production, and GSH depletion.
• Genetic or pharmacological inhibition of STING reversed these metabolic alterations.
• STING was found to interact with FASN, promoting de novo fatty acid synthesis, which is further processed by SCD2 and ACSL4.
• This process generates unsaturated fatty acids, leading to peroxidation and cellular damage.

Conclusions:

• STING activation plays a critical role in reprogramming host lipid metabolism during S. aureus infection.
• STING promotes fatty acid synthesis and subsequent oxidative stress, impacting host defense.
• Targeting STING offers a potential therapeutic strategy for managing metabolic dysregulation in infectious diseases and developing anti-inflammatory treatments.