Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1

Hypercapnia, elevation of the partial pressure of CO 2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO 2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro . Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnia’s effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO 2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.