The role of T cell leptin signaling in 2009 pandemic H1N1 influenza infection mortality in obese mice (VIR2P.1013)

Abstract

Abstract Obese humans are more susceptible to death from infection with the 2009 pandemic H1N1 influenza virus (pH1N1) compared with healthy weight individuals. To identify explanatory mechanisms, we utilized a mouse model of obesity and pH1N1 infection. Diet-induced obese C57BL/6J male mice and lean control mice were intranasally infected with influenza A/Cal/07/09 (pH1N1). Obese mice exhibited an 80% mortality rate, whereas no lean mice succumbed. During the infection, obese mice exhibited similar levels of lung viral titers but had elevated levels of lung inflammatory cytokines and greater lung airway damage. Further, obese mice had fewer activated lung CD4+Foxp3+CD103+ regulatory T cells. As a potential mechanism for the heightened inflammatory responses in the lungs of obese mice, we addressed the role of leptin, an immunomodulatory hormone chronically elevated in an obese state. Obese mice had more than twice as much leptin in serum and lung airways during the pH1N1 infection compared with lean mice. Given the regulatory role of leptin in T cell activity, we utilized mice lacking functional leptin receptor in T cells (LepRT-/-). LepRT-/- and LepRTfl/fl littermate controls were maintained on a high fat or low fat diet for 15 weeks. Preliminary studies indicate that disruption of leptin signaling in T cells limits pH1N1 mortality and infection severity in obese mice. Therefore, leptin signaling in T cells may be a critical mediator of pH1N1 severity in obese mice.