Obesity-Driven Lung Lipidome Remodeling Suppresses NK Cell Activation and Antiviral Immunity to Influenza Infection

SUMMARY Obesity is a major risk factor for severe influenza A virus (IAV) infection, however, the innate immune mechanisms underlying this increased vulnerability remain unclear. Here, we identify significant defects in natural killer (NK) cell antiviral responses in mice with diet-induced obesity. In lean mice, NK cells are critical for protection as NK cell depletion during IAV infection led to increased lung viral load, morbidity, and mortality. In contrast, in obese mice NK cell depletion had minimal impact on viral replication or survival. Notably, IAV infection in obese mice recapitulated the phenotype observed in NK cell-depleted lean mice, indicating that obesity is associated with preexisting NK cell dysfunction. Following IAV infection, obese NK cells in the lung were functionally impaired with diminished activation (CD69 + ), cytokine production (IFN-γ), and cytolytic activity (Granzyme B) accompanied by defects in the mTOR signaling pathway and reduced glycolytic and oxidative metabolism. Bulk and spatial lipidomics revealed obesity and infection-driven remodeling of the lung lipidome. We observed increased triglyceride accumulation, abundance of long-chain free fatty acids, and a shift toward monounsaturated phospholipid species, reshaping the lung microenvironment that coincides with NK cell metabolic dysfunction. Consistent with this lipid-rich environment, obese NK cells sustained high expression of the lipid transporter CD36 post-IAV infection and accumulation of intracellular lipids (LipidTOX + ), consistent with mechanisms known to suppress NK cell function. Notably, short-term weight loss (4 weeks) was sufficient to restore NK cell metabolism, antiviral function, and survival following IAV infection. These findings uncover a lipid-associated mechanism regulating NK cell function and show it plays a critical role in defense against infection and that it is dysfunctional in obesity. We suggest that targeting immunometabolism could lead to new antiviral therapies and potentially improve vaccine efficacy, especially in high-risk populations such as obesity. GRAPHICAL ABSTRACT