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Review
. 2020 Jul;2(7):572-585.
doi: 10.1038/s42255-020-0237-2. Epub 2020 Jun 30.

A metabolic handbook for the COVID-19 pandemic

Janelle S Ayres  1
Affiliations
Review

A metabolic handbook for the COVID-19 pandemic

Janelle S Ayres. Nat Metab. 2020 Jul.

Abstract

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.

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Conflict of interest statement

The author declares no competing interests.

Figures

Fig. 1
Fig. 1. The disease phases of patients with COVID-19.
After infection, patients can remain healthy and show no signs of sickness (maintenance of health). For patients who become symptomatic, the disease course can be described by four stages. Stage 1 is mild, and patients exhibit fever, malaise and a dry cough. Stage 2 is characterized by a pneumonia phase without or with hypoxia (2a and 2b). Patients who progress further along the disease course develop acute respiratory distress syndrome, shock or multiorgan failure (stage 3 III). Patients who recover (stage 4) from the infection show a resilience phenotype. Some patients may never return to their original health state, thus establishing a new baseline for health. Patients who peak in stages 1 or 2 will bypass stage 2 or 3, respectively, and enter into their recovery phase.
Fig. 2
Fig. 2. The parallels among metabolic syndrome, T2D and COVID-19.
COVID-19, metabolic syndrome and T2D are multisystem diseases. The pathologies and pathophysiologies of metabolic syndrome and T2D affect the same systems that are damaged by COVID-19, thus probably predisposing patients to developing more severe pathology during the infection. Importantly, whereas we traditionally think about how metabolic syndrome and T2D make individuals more susceptible to infections because of diminished immune function, an understanding of the parallels between these conditions from a physiological perspective suggests that the greater susceptibility of these individuals to COVID-19 is likely to be partly because of an increased susceptibility to pathology and the resulting pathophysiology, rather than an inability to control the viral infection. COPD, chronic obstructive pulmonary disease.
Fig. 3
Fig. 3. Long-lasting effects of COVID-19 on metabolic health.
Damage caused by COVID-19 and related treatments can harm various systems in the body and may have long-lasting mental, emotional and physiological effects; these effects may result in metabolic abnormalities that hinder the recovery process.
Fig. 4
Fig. 4. Relationship between disease stage and therapy for patients with COVID-19.
After SARS-CoV2 infection, the virus replicates and reaches peak levels during stage 1, after which the levels steadily decline–. As viral levels decline, the host inflammatory response increases during the hyperinflammatory phase. Eventually this response decreases, and the recovery phase of the disease begins. An examination of the relationships among these parameters and the clinical course of the infection dictates which defence strategies will be most effective. Before infection, avoidance is the most clear defence strategy. After infection, patients will be in a presymptomatic (presymp.) phase of the infection, which is followed by stage 1 with fever, malaise and other mild symptoms. The viral levels peak and continue to decline as patients exit stage I, independently of whether patients will recover or progress to a severe or critical stage of infection. Antivirals are most effective for asymptomatic individuals and patients in stage 1. By stage 2, the host inflammatory response drives the disease, which continues into stage 3. Disease-tolerance and antivirulence strategies are most effective for patients in stages 2 and 3. Should patients survive, the host inflammatory response subsides, and the resolution phase begins; patients proceed toward recovery in stage 4. Disease-tolerance drugs are most effective for patients in stage 4. Patients who peak in disease severity in stages 1 or 2 can bypass stage 2 or 3, respectively, and enter into the recovery phase.
Fig. 5
Fig. 5. A framework for defence strategies against COVID-19.
The ability of an infection to cause disease is largely dependent on the host response to the infection. Defensive health mechanisms evolved to promote maintenance or resilience in people challenged with infections. These inducible mechanisms operate by enabling organisms to antagonize or withstand the pathogen. Antagonizing the pathogen is mediated by avoidance and resistance strategies. Avoidance mechanisms are innate and learned behavioural mechanisms that are largely triggered by sensory cues and prevent a host from becoming infected with a pathogen. Resistance mechanisms are encoded by the immune system and destroy the pathogen after it has infected the host. Withstanding the pathogen is mediated by disease-tolerance and antivirulence strategies—physiological defences that alleviate the fitness costs of the infection by limiting physiological damage and promoting health in the presence of the pathogen. Antivirulence mechanisms are a neutralization strategy based on changes in host physiology that limit pathogenic signals during infection without affecting the pathogen’s ability to infect or replicate in the host,,. Disease-tolerance mechanisms limit damage during infection by minimizing tissue susceptibility to damage cues, thus supporting maintenance of physiological function and promoting repair,. A critical distinction is the ways in which these strategies affect the health trajectory with respect to pathogen fitness: avoidance and resistance mechanisms promote maintenance or resilience by avoiding or eradicating the pathogen, whereas disease-tolerance and antivirulence mechanisms promote health by allowing the presence of the pathogen to be withstood. This same framework is important for understanding public-health and medical interventions for COVID-19 that will influence patient disease course. For COVID-19, progression into severe and critical stages of the disease is driven by the hyperinflammatory response resulting from host resistance defences against the infection. Antivirulence strategies will neutralize these pathogenic signals to minimize damage. Disease-tolerance strategies will provide physiological defence in the face of these signals. Quarantines, physical-distancing and hygienic measures serve as avoidance strategies.
Fig. 6
Fig. 6. Targeting host metabolism to defend against COVID-19.
Individuals can use four defence strategies against COVID-19. Avoidance mechanisms prevent an individual from acquiring the infection. Although these mechanisms are likely not to be driven by metabolic processes, the collateral damage from using some avoidance mechanisms can detrimentally affect metabolic health. Resistance strategies protect the host by destroying the infection. Various aspects of host metabolism can potentially be targeted to inhibit viral replication in the host cell and to boost the immune response of the host to destroy the pathogen. Targeting host metabolism may also be a viable strategy to promote both antivirulence defences to protect against pathogenic signals induced during the infection and disease-tolerance defences that limit tissue susceptibility to damage signals and enable them to function despite potentially experiencing damage, as well as to recover from the damage. T2AECs, type II alveolar epithelial cells; ROS, reactive oxygen species.
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