Physiological Mechanisms of Ketone Bodies Relevant to Severe Respiratory Viral Infection and the Syndromes of Critical Illness
https://www.cell.com/action/showPdf?pii=S2666-6340%2820%2930013-1
Metabolic therapies represent novel strategies that could be used to target viral disease progression. In the last decade, the field of immunometabolism research has uncovered multiple points where metabolism influences host-pathogen interactions, not only in altering infection risk and viral replication but also affecting the response of specific immune cell types, thus profoundly controlling disease outcomes. One metabolic therapy with promise in this area is the induction of a state of ketosis, where blood ketone body concentrations are elevated. Ketone bodies are endogenous molecules synthesized from free fatty acids. The primary ketone body, beta-hydroxybutyrate (BHB), directly acts as both a highly efficient oxidative fuel and signaling metabolite. BHB has been shown to have diverse molecular effects, including metabolic regulation; increased cellular resistance to oxidative stress; inhibition of nuclear factor κB (NF-κB) signaling via HCAR2 receptor binding ; decreased activity of components of the innate immune system, such as the nonobese diabetic (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome; decreased systemic inflammatory burden; modifying gene expression; and acting as a fuel in the context of energetic stress. Ketogenic interventions have been used for decades in the treatment of intractable epilepsy and are under clinical investigation for their possible roles in targeting mechanisms of aging and utility in managing diabetes, heart failure, neurodegeneration, and other diseases. A recently registered clinical trial proposed use of ketogenic nutrition in intubated COVID-19 patients (NCT04358835). These multifaceted metabolites are not panaceas, but their pleotropic activities at the interface of aging, metabolism, and inflammation may be useful in mitigating aspects of respiratory viral infection, particularly among patients most susceptible to severe disease.
