Metabolic dysfunction impairs NK cell activation during influenza infection in diet-induced obesity 4686

Abstract Description Obesity is a global health issue, increasing susceptibility to viral infections. Obese mice have increased mortality and morbidity from influenza (IAV) infection due to increased viral spread and lung damage. However, the specific innate immune responses contributing to increased disease severity in obesity remain unknown. NK cells are crucial for defense against viral infections, including IAV. Depletion of NK cells during IAV infection increases mortality with higher viral loads in lean but not obese mice, indicating NK cell dysfunction in obesity. In response to IAV, NK cells in obese mice displayed significantly reduced function, as evidenced by diminished activation (CD69+), cytokine production (IFN-γ), and cytolytic activity (granzyme B). We observed defects in the mTOR-p6SK pathway in obese NK cells that are crucial for antiviral function alongside decreased mitochondrial mass, indicating impaired metabolic function. Obese NK cells maintained high expression of the lipid transporter CD36 post-IAV infection, resulting in an accumulation of intracellular lipids (LipidTOX+), which is known to hinder NK cell function. Preliminary lipidomics studies show elevated and altered species of phospholipids in the bronchoalveolar lavage and lungs of obese mice compared to lean, resulting in a lipid-rich environment that might drive NK cell dysfunction in obesity. These findings suggest that targeting immunometabolism could lead to new antiviral therapies in high-risk populations. Funding Sources 1F32AI183804, 5T32AI106700, CEIRR 75N93021C000016 Topic Categories Viral Immunology (VIR)