Cellular and Biochemical Pathogenic Processes in Severe Influenza Virus Infection: How Does Cytokine Storm Play a Role?

Influenza A virus is one of the most common infectious pathogen and associated with significant morbidity and mortality. Infected patients with underlying diseases show rapid progression in disease severity. The initial pathogenic process of influenza virus infection is characterized by the induction of various proinflammatory cytokines as well as host cellular trypsin-type viral envelope-processing proteases in the airway, which enhance viral multiplication. This process has been termed the “influenza virus−cytokine−trypsin” cycle. In the advanced stage of infection, the cytokine storm induces disorders of glucose and lipid metabolism in the mitochondria, resulting in ATP crisis and various functional disorders particularly in organs and cells with high ATP consumption, such as vascular endothelial cells and cardiomyocytes. This process has been termed interconnection of the “metabolic disorders−cytokine” cycle with the “influenza virus−cytokine−trypsin” cycle. The interconnection exacerbates mitochondrial ATP crisis and could lead to multiple organ failure with severe edema. Breaking these cycles and interconnection is a promising therapeutic approach against severe influenza. In this review, we discuss the pathogenesis of severe influenza viral infection based on animal experiments and the potential therapeutic options.