The role of glucose restriction in host antiviral defense remains elusive. Here, we investigate the impact of pre-existing hypoglycemia on host susceptibility to influenza infections. We find that mouse models with intermittent hypoglycemia exhibit heightened vulnerability to influenza A virus (IAV) infections at low to moderate exposure levels. This vulnerability is attributed to reduced expression of TRIM5 in the lung subsequent to hypoglycemic stress. Hypoglycemic stress activates AMPK protein to down-regulate ERK1/2 signaling and inhibit the transactivation activity of AP-1, thereby suppressing Trim5 transcription. Diminished expression of TRIM5 renders the animals more susceptible to influenza infections as it compromises pulmonary antiviral immunity by attenuating type I interferon (IFN-I) production and signaling. These findings provide mechanistic insights into how pre-existing hypoglycemia detrimentally impacts host antiviral defense, and establish TRIM5 as a molecular link connecting metabolic stress to innate antiviral immunity.
© 2026. The Author(s).