Context and Significance
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.
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.

Graphical Abstract

Background
Respiratory viral infection represents an ever-present public health threat, which can readily overwhelm our existing tools to prevent spread and widespread fatalities. Not only must we deal with seasonal outbreaks, such as respiratory influenza A virus (influenza), but throughout human history, we have faced the regular emergence of novel viruses with global pandemic potential, such as 2003 severe acute respiratory syndrome (SARS)-CoV, 2004 N5N1 influenza, 2009 H1N1/09 influenza, 2012 Middle East respiratory syndrome (MERS)-CoV, and most recently 2019 SARS-CoV-2. Influenza causes more than 20,000 deaths annually in the United States, incurring an economic burden in excess of $87 billion each year.1,2 Similarly, the 2019–2020 global pandemic of the novel coronavirus SARS-CoV-2, causative agent of COVID-19 respiratory disease, in only a few months infected millions of people, killed hundreds of thousands, and led to worldwide social and economic disruption. There is no efficacious universal vaccine for influenza or for SARS coronaviruses (SARS-CoV, SARS-CoV-2, and MERS); consequently, novel therapeutic approaches are vital for the treatment of these viral diseases.
Several population sub-groups appear to be at particularly high risk of complications with respiratory viral infections, such as influenza and SARS-CoV-2. First, older adults have increased risk of hospitalization and mortality.3, 4, 5, 6, 7, 8 Second, patients with diabetes (both type 1 and type 2) also appear to be particularly vulnerable5,9, 10, 11, 12; hallmarks of diabetes include hyperglycemia, glycemic variability, and/or insulin dysregulation, all shown to worsen outcomes from infection.13, 14, 15, 16, 17, 18, 19
Respiratory viruses, including influenza and SARS-CoV-2, can lead to acute respiratory distress syndrome (ARDS)20,21 and death from respiratory failure. ARDS is a complex syndrome that is characterized by lung vascular endothelial injury and alveolar epithelial injury and is associated histologically with alveolar filling with protein-rich fluid.22 The pathophysiology of ARDS includes complex host-pathogen immune interactions along with cellular damage and death resulting from a delayed, pathological hyperactive inflammatory response, hyperoxia, hypoxia, and oxidative stress.23 There is a critical need for mitigation strategies that attenuate these damage pathways, importantly without compromising the early, protective physiological immune response to viral infection. Even patients who recover from critical illness and ARDS can have long-term health consequences from prolonged critical illness, including cognitive impairment and physical disability, exacerbated with age,24,25 reinforcing that clinical strategies should focus on not only mitigating the acute disease process but also on supporting recovery.26
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.27, 28, 29, 30 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.31 BHB has been shown to have diverse molecular effects, including metabolic regulation;32 increased cellular resistance to oxidative stress;33, 34, 35 inhibition of nuclear factor κB (NF-κB) signaling via HCAR2 receptor binding36, 37; 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;38, 39, 40 decreased systemic inflammatory burden;41 modifying gene expression;33,42 and acting as a fuel in the context of energetic stress.43,44 Ketogenic interventions have been used for decades in the treatment of intractable epilepsy45 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.31,46 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.
Blood ketone levels are normally only elevated during a period of fasting or when following a ketogenic diet (between 0.5 and 8 mM).47 It is important to distinguish between “physiological” levels of ketosis,48 which is an adaptive, regulated response to lowered carbohydrate availability and can be safely sustained over many months,45,49 and the acute pathological condition of ketoacidosis. In ketoacidosis, a fundamental metabolic derangement (such as insulin resistance or substance abuse) leads to uncontrolled ketone production and to ketone accumulation, which becomes a medical emergency.50 Barriers to the implementation of novel dietary strategies to trigger controlled, physiological endogenous ketosis, such as fasting or ketogenic diet, include difficulty with adherence51,52 and potential complications in disease states,53 especially when there may be a higher risk of promoting dysregulated ketoacidosis. For example, undernutrition and prolonged fasting can be harmful when applied to the intensive care unit (ICU),54,55 and infection (including COVID-19) may cause metabolic derangements that lead to development of ketoacidosis.56,57 Notably, acidosis itself is associated with mortality in COVID-19 patients,