It is well established that within the context of infectious diseases, both host and pathogen impact each other’s metabolism. Viral diseases, such as COVID-19, perfectly exemplify this, as the virus hijacks host cells in order to survive and replicate. Consequently, viral infection affects metabolic regulation of not only affected cells, but also systemic metabolism.
The importance of metabolism in infectious diseases is also apparent in COVID-19, where individuals with metabolic syndrome, diabetes and hypertension are at greater risk for developing a severe disease course. This can in part be attributed to weakened immune systems in these patients. Yet, a closer look reveals an overlap of pathophysiological processes affected in COVID-19 and metabolic diseases.
In a previous article, we proposed various metabolic pathways as relevant to identify pathophysiologies that mediate outcomes in COVID-19 patients. In this article, we place selected metabolic processes in the context of the rapidly evolving body of knowledge about this disease. We highlight aspects of metabolic dysregulation that render patients with poor metabolic health more susceptible to a severe COVID-19 course.
In doing so, we gain more than just a better understanding of disease pathophysiology. A better grasp of COVID-19 pathophysiology can also provide targets for improving health and vaccination strategies, as well as to identify potential biomarker signatures predictive of long-term complications.
Insulin resistance, dysregulated glucose metabolism and immune response
Patients who suffer a severe disease course are characterized by an out-of-control immune response known as “cytokine storm”. An increasing amount of evidence suggests that individuals with metabolic disorders, particularly those in whom glucose metabolism and homeostasis are dysregulated, have a higher risk of developing complications from COVID-19. Notably, metabolic diseases are characterized by a chronic inflammatory state, which can impact immune responses in situations like infectious disease.
T-cell responses in the context of COVID-19 have been intensely debated regarding their importance in defining the COVID-19 disease course (ECDC 2020) and it is well-known that metabolism has great importance in T-cell biology (Buck et al., 2015). Byproducts of glycolysis promote cytokine maturation and thereby T-cell proliferation. One such metabolite is 3-phosphoglycerate, a precursor of de-novo serine synthesis that is needed for macrophage IL-1β production (Rodriguez et al., 2019).
The IFN-1 response is induced due to viral infection, as well as hypoglycemia. Curiously, impaired IFN production correlates with a severe COVID-19 course (Hadjadj et al, 2020). In mice, this delayed IFN response was associated with the development of cytokine storm (Acharya et al, 2020). Since a majority of severe COVID-19 patients have T2D or metabolic syndrome, their hyperglycemic status may mediate the delayed IFN-1 response. IFNs are crucial for regulating immune cell activation and function. Thus, impaired IFN production may lead to a shift in macrophages towards inflammation over repair functions.
Metabolic control of inflammation and immunoregulation
Besides the immediate link between metabolic disease and inflammation, immunometabolism has emerged as a major research field in itself. It is thus unsurprising that metabolic homeostasis has effects on the immune response to COVID-19, and that COVID-19 has immediate and possibly long-term impacts on metabolism. In the following paragraphs, we will discuss selected pathways involved in inflammatory signaling and immune regulation.
- Immunomodulatory amino acids
Urea Cycle intermediates: In viral hepatitis, the IFN-1 response alters urea cycle metabolism to achieve ornithine and arginine levels that are suitable to regulate adaptive immunity and limit tissue-damage (Lercher et al, 2019). However, these protective effects may be absent in COVID-19, due to the delayed IFN-1 response. At the same time, metabolic syndrome leads to decreased arginine availability and an elevated Arg/Orn ratio (Moon et al, 2017). Collectively, this synergistic impact on urea cycle metabolism may exacerbate tissue damage in patients with severe COVID-19. In fact, this is supported by findings that the urea cycle is dysregulated in severe COVID-19 patients (Thomas et al., 2020).
- Tryptophan metabolism
The main pathway for tryptophan (Trp) degradation is via Indoleamine-2,3-dioxygenase (IDO). Proinflammatory cytokines like IL-6 induce the pathway (Anderson et al., 2013) in response to various conditions. IDO serves to modulate Trp levels by producing kynurenine (Kyn) and its downstream metabolites. Thus, the Kyn/Trp ratio (KTR) directly reflects IDO activity.
As IDO is induced by proinflammatory cytokines, the KTR is often used to indicate inflammation and immune responses in various diseases. The KTR has been used as a prognostic marker of pulmonary TB infection (Cho et al, 2020) and was shown to distinguish patients with a severe COVID-19 course (Thomas et al., 2020). An elevated KTR was also predictive of severity and progression in diabetic kidney disease, as well as treatment response (Wu et al, 2020; Chou et al, 2017). Notably, kidney injury is both a common result of severe COVID-19 disease and a typical diabetic complication.
mTOR activating amino acids: Essential amino acids, especially leucine and other branched-chain amino acids (BCAA), serve as regulators of immunity via activation of mTORC1 (Ananieva et al., 2016). In addition, glutamine (Gln) availability is necessary for the functionality of the mTORC1 complex, showcasing the role of mTOR in sensing nutrient and energy availability to maintain immunity as well as growth
- Lipid inflammatory mediators
Ceramides are sphingolipids involved in inflammatory signaling and are important for maintaining a balanced immune response (Maceyka & Spiegel, 2015). It is appreciated that other lipid species are also involved in inflammatory signaling, via mechanisms that are not completely understood.
- Nuclear receptor ligands
PPAR-γ is best known for its role in regulating lipid metabolism but is also involved in transcriptional control of immune pathways. Its ligands include arachidonic acid and other fatty acids.
Also, PPAR-γ regulates bile acid synthesis via FGF-21. Bile acids, in turn are ligands of the FXR receptor, which is involved in local immune regulation in tissues that express FXR, including lung arterial endothelial cells. Bile acids have been discussed as potential therapeutic targets in lung diseases (Comeglio et al., 2017).
Finally, the immune modulatory role of glucocorticoids is well-established, and the role of steroid hormones is of interest in COVID-19 research not least due to the entry of SARS-CoV-2 via a receptor involved in the Renin-Angiotensin-Aldosterone System (RAAS).
For a more extensive review and further literature on immune regulation by nuclear receptor signaling, a publication by Chinenov et al. (2013) is recommended.
Mitochondrial function in metabolic control and lung homeostasis
Mitochondria are well known for their role in energy homeostasis. Also, oxidative stress has effects on inflammatory signaling via NF-Kappa B. As we discuss subsequently, mitochondrial function affects lung tissue in several ways:
Like COVID-19, COPD is also a disease characterized by chronic airway and systemic inflammation and roughly half of COPD patients exhibit metabolic syndrome. A recent study discovered biomarker signatures predictive of new-onset metabolic syndrome in COPD. These included altered energy metabolism, in which amino acids and fatty acids were preferred over glucose (Holz et al, 2020). It is possible that these metabolic signatures could also predict similar outcomes in COVID-19.
Mitochondrial Gln metabolism is a major pathway for energy homeostasis. Proliferating cells, including immune cells, rely on Gln availability for roles in regulating inflammation, tissue infiltration and cytokine production (Cruzat et al., 2018). Reduced levels have been reported in sepsis (Newsholme, 2001).
Moreover, accumulation of succinate from glutaminolysis can result in sustained IL-1β production. Succinate also enables alveolar epithelial cells (AECs) to adapt to lung injury by enhancing energy production. This is accomplished by increasing flux through glycolysis, the TCA cycle and mitochondrial respiration (Eckle et al, 2013). At the same time, mitochondrial fatty acid oxidation can promote AEC survival and repair in response to acute lung injury (Cui et al, 2019).
Summary
Patients with cardiometabolic co-morbidities are at greater risk for a severe disease course in COVID-19. Metabolomics has the potential to greatly contribute to the understanding of this risk profile. In this article, we reviewed how altered glucose metabolism – one of the main hallmarks of metabolic diseases – are associated with alterations in immune regulation. We also looked at several pathways involved in immunity and inflammation – many of which are affected by metabolic disease. Finally, we touched on the role of mitochondrial function in metabolic disease and lung homeostasis.
References
Acharya, D., Liu, G. & Gack, M.U.: Dysregulation of type I interferon responses in COVID-19. (2020) Nat Rev Immunol | https://doi.org/10.1038/s41577-020-0346-x
Ananieva, E. A., Powell, J. D., & Hutson, S. M.: Leucine Metabolism in T Cell Activation: mTOR Signaling and Beyond. (2020) Advances in nutrition | https://doi.org/10.3945/an.115.011221
Anderson G, Kubera M, Duda W, Lasoń W, Berk M, Maes M.: Increased IL-6 trans-signaling in depression: focus on the tryptophan catabolite pathway, melatonin and neuroprogression. (2013) Pharmacol Rep. | https://doi.org/10.1016/S1734-1140(13)71526-3
Buck, M. D., O’Sullivan, D., & Pearce, E. L.: T cell metabolism drives immunity. (2015) The Journal of experimental medicine | https://doi.org/10.1084/jem.20151159
Chinenov, Y., Gupte, R., & Rogatsky, I.: Nuclear receptors in inflammation control: repression by GR and beyond. (2013) Molecular and cellular endocrinology | https://doi.org/10.1016/j.mce.2013.04.006
Cho Y, Park Y, Sim B, Kim J, Lee H, Cho S-N et al.: Identification of serum biomarkers for active pulmonary tuberculosis using a targeted metabolomics approach. (2020) Sci Rep 2020 | https://doi.org/10.1038/s41598-020-60669-0
Cui H, Xie N, Banerjee S, Ge J, Guo S, Liu G.: Impairment of Fatty Acid Oxidation in Alveolar Epithelial Cells Mediates Acute Lung Injury. (2019) Am J Respir Cell Mol Biol | https://doi.org/10.1165/rcmb.2018-0152OC
Chou C-A, Lin C-N, Chiu DT-Y, Chen I-W, Chen S-T.: Tryptophan as a Surrogate Prognostic Marker for Diabetic Nephropathy. (2018) J Diabetes Investig | https://doi.org/10.1111/jdi.12707
Comeglio P, Morelli A, Adorini L, Maggi M, Vignozzi L.: Beneficial effects of bile acid receptor agonists in pulmonary disease models. (2017) Expert Opin Investig Drugs | https://doi.org/10.1080/13543784.2017.1385760
Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., & Newsholme, P.: Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. (2018) Nutrients | https://doi.org/10.3390/nu10111564
ECDC 2020: Immune responses and immunity to SARS-CoV-2 . (2020) | retrieved from https://www.ecdc.europa.eu/en/covid-19/latest-evidence/immune-responses
Eckle, T. et al.: HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. (2013) | https://doi.org/10.1371/journal.pbio.1001665
Hadjadj, J. et al.: Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients. (2020) | https://doi.org/10.1101/2020.04.19.20068015
Holz O, DeLuca DS, Roepcke S, Illig T, Weinberger KM, Schudt C, Hohlfeld JM.: Smokers with COPD Show a Shift in Energy and Nitrogen Metabolism at Rest and During Exercise. (2020) Int J Chron Obstruct Pulmon | https://doi.org/10.2147/COPD.S217474
Lercher, Alexander; Bhattacharya, Anannya; Popa, Alexandra M.; Caldera, Michael; Schlapansky, Moritz F.; Baazim, Hatoon et al.: Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function. (2019) In Immunity | https://doi.org/10.1016/j.immuni.2019.10.014
Maceyka, M., & Spiegel, S.: Sphingolipid metabolites in inflammatory disease. (2014) Nature | https://doi.org/10.1038/nature13475
Moon J, Kim OY, Jo G, Shin M-J.: Alterations in Circulating Amino Acid Metabolite Ratio Associated with Arginase Activity Are Potential Indicators of Metabolic Syndrome: The Korean Genome and Epidemiology Study. (2017) Nutrients | https://doi.org/10.3390/nu9070740
Newsholme P.: Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? (2001) J. Nutr. | https://doi.org/10.1093/jn/131.9.2515S
Rodriguez AE, Ducker GS, Billingham LK, Martinez CA, Mainolfi N, Suri V, Friedman A, Manfredi MG, Weinberg SE, Rabinowitz JD, Chandel NS.: Serine Metabolism Supports Macrophage IL-1β Production. (2019) Cell Metab. 2019 | https://doi.org/10.1016/j.cmet.2019.01.014
Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA, Spitalnik SL, D’Alessandro A.: COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. (2020) JCI Insight. | https://doi.org/10.1172/jci.insight.140327
Wu M-H, Lin C-N, Chiu DT-Y, Chen S-T.: Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease. (2020) Diagnostics | https://doi.org/10.3390/diagnostics10040207