191-LB: Influenza Replication Dependent on Host Cell Pulmonary Metabolism

Diabetes is an independent risk factor for severe respiratory infections, including influenza (IAV) . We hypothesize that hyperglycemia predisposes diabetic subjects to excess glucose in the airway, allowing for greater IAV replication. To test this hypothesis, type 1 (T1Dx) and type 2 (T2Dx) diabetic mouse models were intranasally infected with influenza. Subsets of T1Dx and T2Dx mice were treated with insulin or metformin, respectively, to restore euglycemia. Glucose concentrations of the bronchoalveolar lavage fluid (BALF) were measured with a glucose oxidase assay. Human bronchial epithelial cells (HBECs) were incubated with varying glucose concentrations, 2-deoxyglucose, AMPK modulators, or insulin, then infected. Viral loads were determined by immunofluorescence and/or qrtPCR for the viral protein hemagglutinin. In vivo, diabetic and infected mice demonstrated increased glucose concentrations in BALF. Viral load was significantly greater in lung homogenates of both T1Dx and T2Dx mice, which was rescued by insulin and metformin treatment. In vitro, HBECs incubated in higher [glucose] had a significantly greater percentage of cells infected than those incubated in normal [glucose]. Conversely, cells treated with 2-deoxyglucose demonstrated reduced IAV replication. Activation of glycolysis using Metformin or AICAR (i.e. AMPK activators) increased IAV replication in a time-dependent manner, while inhibition of AMPK decreased IAV replication. Finally, insulin treatment modulated IAV replication in a similar time-dependent manner. These novel findings suggest that: 1) hyperglycemia increases BALF [glucose] and 2) influenza viral replication is dependent on host-cell glycolysis. Better understanding of the mechanisms altering glucose metabolism during IAV infection may lead to the discovery of novel therapeutic targets for diabetic patients infected with IAV. Disclosure M. Rochowski: None. S. M. F. Allen: None. A. Campolo: Employee; Alcon Research, LLC. V. Lacombe: None. Funding Centers of Biomedical Research Excellence