Anorexia triggered by SARS-CoV-2 causes systemic metabolic changes. In a study published in Nature, Karagiannis et al. demonstrate that the ketones body, b-hydroxybutyrate (BHB) helps improve COVID-19 outcomes. Additionally, BHB metabolically and functionally modifies cells that are CD4 + T cells, which demonstrates the immune-metabolic tuning that occurs in COVID-19.
Anorexia induced by infections is an evolutionary preserved sickness behavior that may be a mediator of harmful or protective immune functions. 1.. Fasting , which includes anorexia cause biochemical changes in the metabolism of fuel which includes the production of ketones. It is linked to a reduction in diseases symptoms in the cardiovascular and cancer diseases and neurodegenerative diseases. 2.. In the absence of food the ketone body is b-hydroxybutyrate (BHB) is created in the liver through the b-oxidation of free-fatty acids, and is it is absorbed as an alternative source of energy by peripheral tissues like heart, muscles and the brain. Evidence suggests that BHB is not just an energy source and is also an molecule that has multiple functions and has cellular communication capabilities, causing direct impacts upon the immune system 3.. While BHB that is obtained from ketogenic diets is associated with improved T cells functioning in human beings 4 However, the extent that it is a contributing factor to the severity of SARS-CoV-2 that is characterised by T cell lymphopenia and deficiency 5 is not yet clear. In a recent study published in Nature, Karagiannis et al. demonstrate that decreased BHB production is associated with diminished cell proliferation + T cells in patients suffering from COVID-19 severe, and BHB supplementation via the ketogenic diet or oral administration of ketone ester improves the survival of the CD4 + T cells and increases their ability to generate interferon-g (IFNg) which in turn boosts the immune system’s ability to fight off viruses 6. (Fig. 1).
Left CD4 + T cells of patients suffering from severe COVID-19-associated ARDS are positive for PD-1 and predominantly skewed toward glycolysis. As the principal carbon source for glucose, it is channeled into the production of pentose and lactate intermediates in the phosphate pathway instead of being absorbed into the TCA cycle, which results in the production of amino acids to a lesser degree and a decreased capacity to create IFNg. When fasting is in place (for example, anorexia induced by infection and ketogenic diet) the ketones body b-hydroxybutyrate (BHB) is produced in the liver using fatty acids . It serves as an alternative source of carbon to provide fuel for the TCA cycle, which results in an increase in mitochondrial OXPHOS and a decrease in glycolysis, thereby increasing the cellular capacity to manufacture IFNg and increasing the immune system’s ability to fight off viruses.
Comparing peripheral blood samples from patients with the acute respiratory distress syndrome (ARDS) caused by influenza, SARS or bacterial respiratory diseases researchers found that those infected by SARS-CoV-2 had significantly lower levels of BHB which indicates ketogenesis dysregulation. As was expected, the serum levels of pro-inflammatory cytokines increased in patients suffering from SARS-CoV-2-induced symptoms contrasted to those who had moderate symptoms or non-infected participants. Interleukin-6 (IL-6) as well as IL-8 was significantly less in ARDS caused by SARS-CoV-2 than those suffering from influenza or bacteria-induced ARDS. This suggests that cytokine-related storms may not be the primary cause in severe COVID-19. Recent studies have demonstrated that severe and moderate COVID-19 is related to an altered metabolism of the body and cellular and decreased concentrations of amino acids, such as Tryptophan as well as cysteine 7,8. So, the researchers further examined the connection of BHB levels and the amino acids. They discovered that BHB supplementation boosted cell counts and improved IFNg production in mouse and human Type 1 Helper (T H1) cells in amino acid deficient conditions in the lab. 6.. In the preclinical model of SARS CoV-2 infection the oral administration of ketone esters through drinking water or ketogenic food regimens enhanced immune CD4 + T cell fitness and viral clearance, which resulted in less lung damage and faster recover from weight loss, and increased the overall life expectancy 6.. The results of this study suggest that BHB is a possible therapeutic option for the treatment of COVID-19 that is severe.
The metabolic alteration of cells is becoming the primary cause to T-cell dysfunction numerous illnesses that include COVID-19 9 and mitochondrial dysfunction. are a hallmark of T cells that are severely sick patients with COVID-19 10. The SCENITH (single-cell metabolic activity by monitoring the inhibition of translation) 11 for single-cell metabolic profiling on the CD4 + and CD8 + T cells of COVID-19 patients The authors found that T cells that were derived from bronchoalveolar fluid showed an incredibly altered metabolic profile that favoured glycolysis, and diminished mitochondrial dependence. Additionally, peripheral blood-derived T cells from patients suffered from diminished capacity to oxidize amino acids as well as fatty acids, suggesting that the capacity of mitochondrial Oxygenative Phosphorylation (OXPHOS) is diminished in T cells of COVID-19 patients. Additionally, decreased cysteine levels could also be a contributing factor to an imbalanced state of redox which could result in impaired T cells’ longevity in COVID-19 severe however this is yet to be examined. So, mitochondrial OXPHOS that is essential to regulate H1 cell function 12 in T T1 cells to functioning 12 is reduced in severe COVID-19, suggesting that both intracellular and cell-extrinsic metabolic changes could affect T cell immunity as well as the severity of disease in COVID-19 as well as other diseases. 9..
Based on the findings the fact that BHB production and responses to T cells were deficient in patients suffering from severe COVID-19 , and that BHB supplementation helped improve outcomes for patients The authors then investigated the way BHB influences T cell metabolic. Through its ketolysis that is carried out via an enzyme called BDH1 (b-hydroxybutyrate dehydrogenase), BHB serves as an alternative metabolic substrate for mitochondrial OXPHOS 13. Therefore, the deficiency of cells in BDH1 reversed the benefits of BHB in T cell survival as well as production of cytokine, suggesting that the enhancement by the CD4 + T cell function through BHB is mostly dependent on the ketolysis mediated by BDH1. The researchers then carried out an array of in vitro studies to show that BHB enhances mitochondrial function. The first was that they demonstrated that BHB-supplemented H1 cells displayed increased maximal and basal mitochondrial respiration as well as spare respiratory capacity, which indicates enhanced mitochondrial OXPHOS. Then, employing SCENITH analysis they found that the T H1 cells showed increased mitochondrial dependence as well as diminished glycolytic capabilities following the addition of BHB. Furthermore, the ability to allow the CD4 + T cells to process amino acids and fatty acids was increased in the presence of BHB. Thirdly, by the kinetic tracer method with the 13C-labelled BHB The authors demonstrated that BHB is integrated into the tricarboxylic acid (TCA) intermediates within T H1 cells. In addition carbons derived of 13C-labelled BHB were also integrated in bioenergetic amino acids (for instance, glutamate and aspartate) and glutathione that is oxidized (GSSG) in line with the upregulated expression levels of genes that encode enzymes involved in metabolic pathways in cells like Cpt1 (fatty acid oxidation), Got1 (amino acid metabolism) as well as Ndufs8 (OXPHOS). However, carbons from the 13C-labelled glucose were only found in glycolytic intermediates such as lactate as well as in the pentose-phosphate pathways. Thus, these findings collectively indicate BHB as a possible alternative carbon source within the CD4 + T cells, which alters the metabolism of cells to enhance mitochondrial function in environments deficient in nutrients.
The differences in ketosis seen in patients suffering from severe COVID-19 and those suffering from influenza is to be assessed. The synthesizing of BHB is tightly controlled in a precise manner, both temporal and spatially through the catalytic expression and activity in BDH1 as well as HMGCS2 (ref. 14) These could be the underlying cause of impaired BHB production in patients suffering from severe COVID-19. Additionally, lower levels of BHB in patients who have recently diagnosed COVID-19 could also function as a predictor for the formation of severe COVID-19 and these patients may be advised to adopt ketogenic diets as a therapy strategy to boost antiviral immunity. In addition, the authors demonstrated they found that PD-1 expression was elevated on T cells isolated from the peripheral blood as well as the bronchoalveolar fluids from patients suffering from COVID-19-related ARDS. They also found the results showed that BHB supplementation decreased PD-1 manifestation on cells both in both in vitro and in the vivo. Because PD-1 is linked with T cell exhaustion or dysfunction in a variety of situations in clinical practice 9 It is interesting to find out whether BHB also affects its expression levels of PD-1 and other exhaustion- or dysfunction-related molecules in different conditions, such as chronic cancers and infections.
In general, this study discovered BHB as a ketone body BHB as a possible alternative source of carbon to fuel mitochondrial OXPHOS and thus metabolically altering the function of cells called T H1 cells and enhancing antiviral immunity under conditions of anorexia induced by infection. With regard to the various cells’ signalling capabilities that are associated with BHB 3. it could be that BHB affects CD4 + T cell function via other mechanisms, like transcriptional regulation or epigenetic modification, in line with the role of BHB in regulating the development of CD8 + memory T cell growth via epigenetic control 15.. Since metabolic programs are key controllers of T cell proliferation and differentiation, including CD4 + and CD8 + T cell morphology as well as heterogeneity 9 Further studies are needed to investigate the possibility that BHB and other metabolites that are triggered by ketogenic diets have similar effects on different types of T cells in the course of infection, or in other contexts deficient in nutrients and the tumour microenvironment. In sum, these crucial results expand our understanding of the influence of diet on antiviral immunity , and offer fresh understanding and insights into the various morbidities related to COVID-19.
