Hypercapnia Inhibits Host Defense Against Influenza A Virus by Potentiating Virus-induced Activation of the PI3K/Akt Pathway

RationaleHypercapnia, the elevation of CO2 in blood and tissue, commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary bacterial and viral infections, including influenza. We previously reported that hypercapnia downregulates several innate immune genes and increases the mortality of bacterial pneumonia and influenza A virus (IAV) infection in mice. High CO2 also increases viral nucleoprotein (NP) expression in the mouse lung, primarily in alveolar macrophages (MOs). In the current study, we explored the effect of hypercapnia on the PI3K/Akt pathway during IAV infection in MOs. In addition, using pharmacologic PI3K and Akt inhibitors we studied the role of hypercapnia-induced activation of Akt on the expression of antiviral proteins, including MX dynamin like GTPase 1 (MX1), 2′-5′-oligoadenylate synthetase 1 (OAS1) and viperin; viral nonstructural 1 protein 1 (NS1) and NP. MethodsHuman alveolar and PMA-differentiated THP-1 MOs as well as murine alveolar and bone...