In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild‐type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR‐3 activation. This evidence concerns the gene TLR3 and viral infectious disease.