Increased mortality from influenza infection in long-chain acyl-CoA dehydrogenase knockout mice

We previously showed that the mitochondrial fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed in alveolar type II pneumocytes and that LCAD−/− mice have altered breathing mechanics and surfactant defects. Here, we hypothesized that LCAD−/− mice would be susceptible to influenza infection. Indeed, LCAD−/− mice demonstrated increased mortality following infection with 2009 pandemic influenza (A/CA/07/09). However, the mortality was not due to increased lung injury, as inflammatory cell counts, viral titers, and histology scores all showed non-significant trends toward milder injury in LCAD−/− mice. To confirm this, LCAD−/− were infected with a second, mouse-adapted H1N1 virus (A/PR/8/34), to which they responded with significantly less lung injury. While both strains become increasingly hypoglycemic over the first week post-infection, LCAD−/− mice lose body weight more rapidly than wild-type mice. Surprisingly, while acutely fasted LCAD−/− mice develop hepatic steatosis, influenza-infected LCAD−/− mice do not. They do, however, become more hypothermic than wild-type mice and demonstrate increased blood lactate values. We conclude that LCAD−/− mice succumb to influenza from bioenergetic starvation, likely due to increased reliance upon glucose for energy.