Abstract
Significance: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer.Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilizes endogenous ROS production via NADPH oxidase (NOX)2-containing NOXs and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilization of hypoxia-inducible factor-1α, promoting interleukin-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle.Critical Issues: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as Streptococcus pneumoniae.Future Directions: Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.
Highlights
The rise of photosynthesis by certain ancient cyanobacteria posed a major challenge to existing life forms, which had to survive a reducing atmosphere, but largely drove the evolution of eukaryotes
This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer
This review focuses on the metabolic and oxidative stress pathways activated by bacteria and viruses; there is no doubt that co-evolution of these pathogens coincides with the initial oxygenation events that occurred more than *2.5 billion years and, as such, adapted to utilizing ROS for their advantage
Summary
The rise of photosynthesis by certain ancient cyanobacteria posed a major challenge to existing life forms, which had to survive a reducing atmosphere, but largely drove the evolution of eukaryotes. As previously mentioned, increased PPP due to the inflammatory status of macrophages generating NADPH, as well as SDH activity driving mtROS, likely provides the cocktail necessary for the induction of an NOX2-dependant oxidative burst, which, though necessary for pathogen clearance, causes great collateral damage (e.g., lung injury). NADPH may not solely be responsible for this communication; there are multiple pro-inflammatory signals that could cause an increase in the activity of NOX2 oxidase Such mediators could include the NLRP3 inflammasome complex, or a product such as IL-1b. It may be plausible that prolonged activation of inflammatory pathways brings about epigenetic changes, leading to increased expression of TLRs, which can more readily and proactively react against invading pathogens [141] One such process could involve metabolic modifications within macrophages and natural killer cells. It resulted in a substantial suppression of neutrophil infiltration and the alveolitis to PR8 infection in mice [168]
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