Severe
influenza is characterized by
cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the
pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of
pyruvate, linking glycolysis to the tricarboxylic acid cycle and
fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of
diisopropylamine dichloroacetate (DADA), a new
PDH kinase 4 (PDK4) inhibitor, in mice with severe
influenza.
Infection of mice with
influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and
ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs.
Oral administration of DADA at 12-h intervals for 14 days starting immediately after
infection significantly restored PDH activity and
ATP level in various organs, and ameliorated disorders of
glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of
cytokine storm,
trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-
cytokine cycle, which is closely linked to the influenza virus-
cytokine-
trypsin cycle, resulting in prevention of multiorgan failure in severe
influenza.