Respiratory viral infections remain a scourge, with seasonal influenza infecting millions and killing many thousands annually and viral pandemics, such as COVID-19, recurring every decade. Age, cardiovascular disease, and diabetes mellitus are risk factors for severe disease and death from viral infection. Immunometabolic therapies for these populations hold promise to reduce the risks of death and disability. Such interventions have pleiotropic effects that might not only target the virus itself but also enhance supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate functional recovery. Ketone bodies are endogenous metabolites that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics. Here, we provide an overview of ketone body biology relevant to respiratory viral infection, focusing on influenza A and severe acute respiratory syndrome (SARS)-CoV-2, and discuss the opportunities, risks, and research gaps in the study of exogenous ketone bodies as novel immunometabolic interventions in these diseases.
Respiratory viral diseases, such as seasonal influenza or COVID-19, are deadly scourges on society. Immunometabolic therapies may be important tools to reduce the burden of death and long-term disability caused by pandemic viruses. Here, we describe the biological effects of ketone bodies, natural metabolites produced during fasting or carbohydrate restriction, that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and gene expression. Several biological actions of ketones may be therapeutically relevant to populations at highest risk of respiratory viral infection but have not been tested in this context; other actions may have counterproductive effects. Notably, ketones can now be easily administered using exogenous ketone compounds, making this a promising area for future research.
Stubbs et al. provide an overview of the known biological actions of ketone bodies that could be relevant to severe respiratory viral infection, using influenza A virus and SARS-CoV-2 as key examples, and describe how exogenous ketones could be a novel immunometabolic intervention in these diseases.
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