Impaired mTOR Signaling Causes Immune Suppression in Diabetes

Abstract

Abstract It is estimated that over 11% of the U.S. population has diabetes and that 38% of the adult population is pre-diabetic. Diabetes carries increased risk and severity of many infections, which has been attributed to defects in the innate immune system. Despite the high impact of diabetes on infection, the underlying mechanisms of immune dysfunction in the diabetic host have yet to be fully elucidated. We have recently shown that innate immune cells in a diabetic host environment cannot undergo respiratory burst of reactive oxygen species and nitric oxide in response to infection with Staphylococcus aureus, the most common pathogen associated with frequently severe and invasive skin and soft tissue infection (SSTI) in patients with diabetes. The inhibition of respiratory burst was due to defects in the activation-dependent expression of the glucose transporter GLUT1, which is required for respiratory burst in neutrophils and macrophages. We therefore sought to further elucidate the specific mechanisms by which phagocytes in a diabetic environment are impaired in their ability to control S. aureusSSTI. We observed that mTOR signaling is impaired in a diabetic mouse model of S. aureusSSTI, which is upstream of both respiratory burst and GLUT-1 expression. Inhibition of mTOR signaling with rapamycin phenocopies the higher bacterial burden during diabetic infection, as well as the inhibition of respiratory burst and GLUT-1 expression. We further observed that mTOR activity upon macrophage activation is impaired in the absence of insulin and growth factor signaling. These findings begin to elucidate a role for mTOR signaling in the mechanism of immune suppression caused by diabetes.