Fig. 1

Viruses like SAR-CoV-2 manipulate cellular metabolism leading to the potential for a feed-forward inflammatory loop. Viruses have evolved to usurp their host’s cellular machinery to make more viruses. One common mechanism is to suppress apoptosis and manipulate the immune system to inhibit specific anti-viral programmes, which usually means interferons, while stimulating a shift towards aerobic glycolysis to provide precursors to build new viruses. However, this latter ability repurposes pathways that are often involved in generalised immunity that both increase the production of pro-inflammatory mediators, while metabolically reprogramming immune cells. In the case of SARS-CoV-2 this may well result in a feed-forward pro-inflammatory loop in the lungs, which seems to be driven by monocytes/macrophages switching to aerobic glycolysis and is driven my mitochondrial ROS and stabilisation of HIF-1α; in turn, this metabolic shift suppresses T-cells and the interferon response [88]. This process is accentuated as the virus may well stimulate inflammasome activation [81], while if it is similar SARS-CoV-1, it could also suppress MAVS formation and activate NF-kB [62]; protein interaction mapping does suggest this is the case [66]. As it is likely that inflammasome activation can also invoke glycolysis [89], then the evolutionary rationale seems sound. Of particular importance here is also the balance between NF-kB and Nrf2, which more or less seem to counter-balance each other, as Nrf2 is pivotal in suppressing excessive oxidative stress [91]. For more detailed reviews of the role of mitochondria in the immune response see [22, 107]