Current work and future possibilities for the management of severe influenza: Using immunomodulatory agents that target the host response

In this article, we argue the case that the excessive inflammatory response seen in severe influenza contributes to severe illness and death by disabling oxidative phosphorylation in mitochondria, leading to reduced cellular levels of ATP. When the mitochondrial permeability transition is induced, cells cannot die by apoptosis in the face of reduced ATP levels, because apoptosis depends upon ATP availability, and so cells undergo necrosis. Cellular necrosis causes release of proinflammatory molecules such as high mobility group box 1 protein and mitochondrial DNA, and these could contribute to the prolongation of inflammation during severe influenza. With these concepts in mind, we discuss how immunomodulatory agents that prevent cellular necrosis (by restoring mitochondrial function) and limit inflammation are promising influenza treatments.