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A metabolic blueprint of COVID-19 and long-term vaccine efficacy

  • Engin Berber ORCID logo EMAIL logo , Deepak Sumbria und Serkan Kokkaya
Veröffentlicht/Copyright: 28. September 2022
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Drug Metabolism and Personalized Therapy
Aus der Zeitschrift Drug Metabolism and Personalized Therapy Band 38 Heft 1

Abstract

Viruses are obligatory protein-coated units and often utilize the metabolic functions of the cells they infect. Viruses hijack cellular metabolic functions and cause consequences that can range from minor to devastating, as we have all witnessed during the COVID-19 pandemic. For understanding the virus-driven pathogenesis and its implications on the host, the cellular metabolism needs to be elucidated. How SARS-CoV-2 triggers metabolic functions and rewires the metabolism remains unidentified but the implications of the metabolic patterns are under investigation by several researchers. In this review, we have described the SARS-CoV-2-mediated metabolic alterations from in vitro studies to metabolic changes reported in victims of COVID-19. We have also discussed potential therapeutic targets to diminish the viral infection and suppress the inflammatory response, with respect to evidenced studies based on COVID-19 research. Finally, we aimed to explain how we could extend vaccine-induced immunity in people by targeting the immunometabolism.

Keywords: COVID-19; immune therapy; metabolic drugs; metabolism; SARS-CoV-2; vaccination

Introduction

Coronavirus disease 2019 (COVID-19) is causing a severe acute respiratory syndrome (SARS) in humans and is responsible for the current pandemic, caused by a recently emerged coronavirus known as SARS-CoV-2 [1, 2]. The origin of this viral strain was speculated to be Hunan seafood market which is an industrial city in China (Hubei province), i.e. Wuhan [3]. Viruses infect cells through several mechanisms but commonly use receptor-mediated mechanisms for entry. Viruses initially cause several changes in the cells they infect, such as controlling mRNA or interacting with protein machineries to favor their replication [4]. Some studies have demonstrated that viral infections can cause long-term changes even when the virus no longer exists [5]. Many viruses, including coronaviruses, hijack cellular mechanisms upon infection to generate their own replicas by manipulating the metabolic processes of cells. Those changes often alter energy metabolism such as glucose and amino acid, or lipid metabolism in cells, inevitably resulting in an alteration in the mitochondrial function [6]. Such metabolic changes caused by viruses were discussed and explained by many respected studies and we briefly summarize some of them in this review.

Several studies have reported that more than 50% of people who died due to COVID-19 had several pre-existing metabolic conditions and suffered more than so-called metabolically healthy SARS-CoV-2-infected patients [7]. What we know about this COVID-19 scenario is that people with pre-existing metabolic conditions are often vulnerable to a severe respiratory syndrome, associated with high mortality ratios [8]. Such conditions include diabetes, obesity and cardiovascular problems (hypertension). In addition, age and gender, which can also cause metabolic changes, are also discussed as risk factors for COVID-19; however, it is not a topic of this review [9].

In molecular mechanistic explanation, there is a direct link between COVID-19 and endocrine system-controlled metabolism due to the virus binding receptor through angiotensin-converting enzyme 2 (ACE2) [10]. ACE2 receptor expression has been found across many organs and cells besides the lungs, such as the pancreas, kidney, and some inflammatory cells [11]. ACE2 is directly connected to endocrine and paracrine regulation through the renin-angiotensin-aldosterone system (RAAS). RAAS not only controls blood pressure and fluid homeostasis physiologically but also prompts many changes such as increases in insulin resistance and inflammation, metabolically. The importance of RAAS and RAAS-associated metabolic changes has already been studied and reviewed in considerable detail [12]. Not only did pre-existing metabolic disorders render people susceptible to severe COVID-19 but SARS-CoV-2 could also cause metabolic dysfunction both on the cellular and host scales, which is the major topic of the current review.

Metabolic changes in SARS-CoV-2 infected cells

Glucose metabolism

Viruses employ various metabolic pathways for their own benefit by manipulating the cellular metabolism [6]. One of the significant changes after viral entry is found in carbohydrate metabolism. Carbon metabolism is a core metabolic process of energy production in ATP synthesis and is employed in glycolysis for rapid ATP synthesis [13]. In fact, infected cells could demand higher energy by elevating glycolysis activity or enhancing glucose uptake [14]. An in-vitro study revealed that SARS-CoV-2 infected Vero E6 cultures significantly enhanced the glucose flux into cells which favored SARS-CoV-2 replication. Notably, this study also shows that SARS-CoV-2 infected cells demand higher glucose utilization, indicating the upregulation of glycolysis [15]. This phenomenon is also known as the “Warburg effect” and is mainly applicable to cancer cells and reviewed for some viruses [16, 17]. SARS-CoV-2 can also show Warburg-like activity in the cells they infect but it needs to be clarified since aerobic glycolysis may be activated in alveolar epithelial cells independent from virus infection, in response to hypoxia. To explain the importance of glucose utilization for SARS-CoV-2, a study has been designed to inhibit glycolysis use by a glucose competitive inhibitor-2-deoxy-D-glucose (2DG) in vitro. Results showed that the inhibition of glucose metabolism diminished the SARS-CoV-2 replication after 2DG treatment [18]. Similar findings were also obtained from others by using colon cancer cells (Caco-2), in which the use of various dose concentrations of 2DG up to IC50 levels (9.09 mM) abrogated the virus replication [19]. An opposing outcome has been observed in influenza (A/WSN/33) virus infected and 2DG treated mice study indicating that inhibition of glucose metabolism is lethal in influenza infection, but prevented bacterial infection (Listeria monocytogenes) [20]. Similarly, 2DG treatment led to increase influenza virus associated acute respiratory distress syndrome (ARDS) symptoms but had no effect on BALF infiltrates [21]. These changes might occur independent of immune response. One of the metabolites found in the glycolysis pathway is lactate which often increases when excessive amounts of glucose are up-taken or broken down by cells [22]. Lactate is converted from pyruvate by enzymatic activity of lactate dehydrogenase (LDH). Codo et al. investigated the effect of LDHA inhibitor (oxamate) in SARS-CoV-2 infected cells and the results showed that inhibition of LDHA completely abolished the viral load and decreased ACE2 and IL-1β expression in infected cells [23] indicating both anti-viral and anti-inflammatory effects of metabolic treatment. The anti-viral outcome of manipulating glucose metabolism during COVID-19 appears to be beneficial to reduce viral burden, however, such clinical interventions should be designed and performed cautiously due to effector immune cells can also be altered when glycolysis is impaired.

Metabolic change in immune cells was also investigated in several studies. One of the well-designed studies showed that SARS-CoV-2-infected monocytes enhanced the level of glycolysis, glycolytic capacity, and glycolytic reserve needed for the promotion of viral replication [23]. In support of the metabolic alteration of cells, many other studies also found that SARS-CoV-2- infected or impacted cells rewire their metabolic functions and eventually become functionally unavailable [24].

Lipid metabolism

One of the most significant energy-producing metabolic processes of living organisms is the lipid metabolism. It either occurs via (i) the catabolic process through beta-oxidation and its entry into the citric acid cycle (TCA) called fatty acid oxidation (FAO); or (ii) building of lipid moiety called fatty acid synthesis (FAS) with peptides such as phospholipids [25].

Coronaviruses are known for forming double-membrane vesicles during replication, assembly, budding and maturation from infected cells [26]. There are several examples with Flaviviridae members, hepatitis C virus (HCV), and Dengue virus which provide evidence that viral infection triggers lipid formation in the infected cells [27]. Similar to these (+) RNA viruses, an in vitro study found using electron microscopy that SARS-CoV-2-infected Vero cells (permissive cell line for SARS-CoV-2) exhibited elevated lipid formation [28]. Accordingly, ex vivo infection of human monocytes with SARS-CoV-2 also exhibited lipid droplet (LD) formation in cells after 24 h of infection [29]. Similar changes were also observed in human lung epithelial and human lung microvascular endothelial cell lines [29]. In an experimental design, Vero cells infected by SARS-CoV-2 also showed more LD, compared to the control cell culture [28].

Regarding the mechanism of action, SARS-CoV-2 causes upregulation of an integral membrane protein called CD36 that facilitates fatty acid and lipid uptake. It also enhances the transcription factors necessary for FAS such as peroxisome proliferator-activated receptor α (PPARγ) and sterol regulatory element-binding protein 1 (SREBP-1) and diglyceride acyltransferase 1 (DGAT-1). In a mechanistic explanation, a recent study showed that the blockade of LD formation (through A922500, an inhibitor of DGAT-1) resulted in a low level of SARS-CoV-2 replication in monocytes. Moreover, the reduction of LD formation through the treatment of A922500 also diminished the formation of leukotrienes (CysLT and LTB4) and some chemokines (IL-8 and CXCL10), along with inflammatory cytokines (IL-6, TNF-α) responsible for the cytokine storm caused by SARS-CoV-2-infected monocytes [29]. It appears that the inhibition of FAS could be beneficial in terms of reducing both viral burden and inflammation. Cholesterols are also a kind of lipids and involve the lipid membrane structure of cells. SARS-CoV-2-infected lung epithelial cells had upregulated an enzyme, cholesterol 25-hydroxylase (CH25H), involving the membrane-lipid cholesterol catabolism as an antiviral response. Similar results were also obtained from samples from severe COVID-19 patients such as sera, PBMCs, and epithelial cells in the same study and by others [30, 31]. These studies and others also showed that overexpression of CH25H by the lung epithelial cells or pre-treatment of cells with CH25H demonstrated the suppression of SARS-CoV-2 viral infection, suggesting that CH25H reduces the moiety of membrane cholesterol level so that cells become inaccessible for viral fusion [30]. Host cell plasma membrane and virus lipid envelope membrane enriched in lipid cholesterol. Viral fusion of SARS-CoV-2 with host cells begin after viral spike protein and ACE2 docking. Cholesterol enriched lipid membranes also play important role in intracellular trafficking of Sars-CoV-2 and budding from cells [32]. In addition, a study has found a cholesterol recognition motif in virus spike protein region that molecularly interact with ACE2 domain showing the importance of cholesterol for viral entry [33]. The cholesterol level can be reduced by the use of various inhibitors of cholesterol synthesis such as statins. The antiviral effects of fluvastatin were also observed in SARS-CoV-2-infected human respiratory epithelial (Calu-3) cells and human primary bronchial epithelial cells [34].

Glutamine metabolism

Information on amino acid metabolism in cells infected with SARS-CoV-2 is limited. The amino acid glutamine provides an input to fuel the TCA cycle and is important for the mitochondria, in the absence of pyruvate [35]. Mullen et al. revealed that the entry of glutamine metabolites into the TCA cycle was reduced in SARS-CoV-2-infected Vero cells. Moreover, infected cells reduced the need for glutamine uptake, but cells compensated by increasing the uptake of glucose to fuel the TCA cycle. The catabolism of glutamine was more prolific in non-infected cell, compared to the infected cell line [24].

Kynurenine (KYN) metabolism

An in vitro study using human lung alveolar adenocarcinoma cells (A549, Calu3 and ACE2) including normal human bronchial epithelial cells showed the upregulation of genes involved in tryptophan metabolism, after infection with SARS-CoV-2 [36]. Tryptophan enzymatically converted into KYN metabolite and was ultimately used for the production of nicotinamide adenine dinucleotide (NAD) synthesis and utilized for the TCA cycle in mitochondria. Thus, SARS-CoV-2 infections supply the TCA cycle through the catabolic processes of tryptophan [37]. An apparent KYN metabolite was found upregulated significantly in the nasal wash specimens of SARS-CoV-2 infected ferrets [38].

Mitochondrial changes

Cellular mitochondrial antiviral signaling protein (MAVS) function is often reportedly interrupted by SARS-CoV-2 proteins, suggesting that the IFN-γ response becomes altered and immunosuppression pronounced [39]. Another study showed that SARS-CoV-2 infection decreases the level of TCA and oxidative phosphorylation (OXPHOS) in most in vitro infected cell lines such as adenocarcinomic alveolar basal epithelial, human adenocarcinomic lung epithelial and bronchial epithelial [36]. An in vivo study on SARS-CoV-2-infected mice investigating mitochondrial functions found the level of TCA and OXPHOS reduced in many organs such as the heart, kidney, spleen, and lung of the infected mice [40]. Similarly, human lung adenocarcinoma cells called Calu-3 showed downregulation of TCA and OXPHOS when infected with SARS-CoV-2 [18]. A study also expanded the understanding of mitochondrial changes in SARS-CoV-2-infected human samples by using transcriptome data analysis of bronchoalveolar lavage fluid and lung specimens [41]. The results revealed that mitochondrial genes and MAVS expression were not plausibly affected; however, marked attenuation was observed in complex I, an enzyme complex of the respiratory chain in mitochondria, and cellular respiration reduced [41]. Apparently, the host cell antiviral function was paralyzed due to reduced mitochondrial respiration, favoring viral production. Codo et al. showed that monocytes infected with SARS-CoV-2 produced more reactive oxygen species (ROS) [23]. ROS is also a known inducer of hypoxia inducible factor 1 alpha (HIF-1α), which plays an important role in anaerobic glycolysis and maintains glycolysis in return [42]. Viral inhibition occurred when monocytes were treated with a ROS inhibitor called mitoquinol [23]. The effects of SARS-CoV-2 infection on host cell metabolism have also been briefly indicated in Figure 1.

Figure 1: Schematic presentation of metabolic changes in cells caused by SARS-CoV-2. SARS-CoV-2 activates glycolysis via upregulation of ROS in mitochondria and limits glutamine uptake [15, 24]. Infected cells were also found with lipid accumulation in cells and increased fatty acid synthesis [28, 29]. Some studies also reported an increase of some KYN metabolites which indicate uptake of tryptophan [37].
Figure 1:

Schematic presentation of metabolic changes in cells caused by SARS-CoV-2. SARS-CoV-2 activates glycolysis via upregulation of ROS in mitochondria and limits glutamine uptake [15, 24]. Infected cells were also found with lipid accumulation in cells and increased fatty acid synthesis [28, 29]. Some studies also reported an increase of some KYN metabolites which indicate uptake of tryptophan [37].

Viruses can decide the cellular fate through metabolic interaction such as controlling mitochondrial ROS [43]. Overproduction and excessive amounts of ROS can be destructive for cells and facilitate irreparable tissue damage [44]. In addition to SARS-CoV-2, other respiratory viruses including influenza A can also result in ROS production in infected cells [45]. HCV, hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are other well-studied examples of overproduction of ROS as a consequence of viral infection [46], [47], [48]. Excessive ROS can lead to the increase of mitochondrial membrane permeability, controlled by B cell lymphoma-2 (Bcl-2) protein family, resulting in the release of cytochrome-c into the cytoplasm [49]. Cytochrome-c is a pro-apoptotic molecule and activates apoptotic cascades [50]. Some studies have shown that adenoviruses, poxviruses, and herpesviruses evolved to control apoptosis by antagonizing Bcl-2 [51, 52]. Some viruses such as Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) can downregulate and suppress the functions of the proteins involved in apoptosis either by the functions of viral proteins or miRNA molecules while maintaining the ROS [53, 54]. It would not be surprising if antioxidant therapeutic approaches gain attention in controlling COVID-19. Such antioxidant vitamin interventions and changes in diet strategies are discussed in next section.

SARS-CoV-2 sets metabolic changes during COVID-19 in humans

Several meta-analysis studies suggest that high blood glucose levels (>180 mg/dL) during admission to the hospital tend to predict poor COVID-19 outcomes even in asymptomatic individuals, regardless of diabetes history [40, 55, 56]. It was also observed that acute hyperglycemia occurred in patients during hospitalization or at admission [55, 57]. Blood glucose could be elevated for several reasons, including (i) viruses damaging the pancreatic islet cells, causing elevated glucose levels due to altered insulin secretion; (ii) inflammatory responses triggered by SARS-CoV-2 can increase the insulin resistance in patients previously observed in SARS, leading to higher blood glucose and (iii) stress-induced hormones could also drive higher blood glucose levels transiently [58]. Moreover, in response to increased blood glucose, cells can upregulate the ACE2 receptor and facilitate the entry of SARS-CoV-2 virions into cells in a receptor-mediated manner [59].

Several studies have averred that an elevated blood lactate dehydrogenase (LDH) during admission or hospitalization might be relevant to predicting critical COVID-19 disease development [60, 61]. LDH is also a predictor factor for COVID-19 [62]. A clinical study evaluated several factors including LDH on 548 COVID-19 patients during admission and found that high-level LDH (>445 U/L) is a significant risk factor associated with death and elevated LDH implied worsening lung injury and tissue damage [63]. However, an increase in blood LDH can be a consequence of cytokine-mediated tissue or cellular damage during severe infections not a direct effect of virus infection.

It is also noteworthy that peripheral blood mononuclear cells (PBMC) in mild and moderately infected individuals showed an increase in lactate production and consumption of glucose, indicating elevated glycolysis in symptomatic patients [64]. Clinical phase studies in India aimed to show that the use of 2DG during COVID-19 could prove beneficial, but results have not been shared, to our knowledge [65]. However, 2DG can potentially suppress immune cell development and reduce the expression of IFN-γ that is needed for host antiviral response [66]. Nevertheless, clinical implications to inhibit glucose metabolism, for instant glucose demanding infected cells, could either be beneficial to reduce viral replication or unfavorable for immune response development.

Lipid metabolism is poorly defined in COVID-19 patients. Interestingly, a study highlighted that there was a long-term dysregulated lipid profile in survivors of mild or severe COVID-19 [67]. Several clinical studies indicate that disease severity and poor prognosis are associated with dyslipidemia in patients during hospitalization and can be predicted on admission [68, 69]. A retrospective single center study in Wuhan examined the lipid profile in severe cases. Study results indicated that the overall lipid profile decreased during disease progression in non-survivors, while it returned to normal in survivors. Study results also implied that low blood lipid level-dyslipidemia was associated with elevated inflammatory response and poor prognosis of COVID-19. Dyslipidemia or hypolipidemia could be an independent indicator of mortality in COVID-19 patients [70]. Mechanistically, it appears that lipid metabolism is needed for infected cells so they uptake more lipids from the environment. Another possible explanation could be the increased inflammatory response. High density lipoproteins (one of the main indicators of blood lipid level) or apolipoproteins have an affinity to enriched lipid rafts on cell membranes such as macrophages (toll-like receptor enriched) and uptake of lipid coated pathogen associated patterns occurs much during acute viral or bacterial infections and subsequently drops in the plasma level. The decrease of plasma lipids seems to be independent of COVID-19 and is mostly associated with the increased inflammatory response to COVID-19. It is also reported that PBMCs collected from COVID-19 patients had more accumulated lipid droplets (LD), especially in monocytes. According to this study, monocytes collected from SARS-CoV-2-infected patients were demonstrated lipid droplet accumulation, compared to healthy patients’ monocytes [29].

Early studies done in mild and moderate SARS-CoV-2 infected patients showed that PBMCs had scored a lower level of glutamate, compared to healthy individuals. They also concluded that the poor T cell responses seen in COVID-19 patients might be correlated with the reduced level of glutamine amino acid due to the involvement of glutamine amino acid in T cell fashion [64]. Other clinical studies focused on the metabolic profile analysis also provided evidence of a strong metabolic signature in COVID-19 patients. One of these studies found a marked effect between the amino acid tryptophan and the KYN metabolites [71]. As an amino acid, tryptophan is converted to KYN through indoleamine 2,3-dioxygenase (IDO) enzyme activity. Mild and critical patients presented a notable increase of KYN acid and anthranilic acid in their sera. An increase in KYN acid is a sign of increased activity of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase enzymes. Activation of this KYN pathway also showed a correlation with increased concentrations of the cytokine IL-6, which drives the disease stage to poor prognosis [72]. These two studies interpreted the results to mean that the diminished tryptophan level in COVID-19 patients is closely associated with a poor prognosis of the disease. The increase of tryptophan utilization and IDO activity by immune cells has an immune-suppressive effect on the system at large [73, 74]. IDO is commonly expressed by the mucosal epithelial cells such as lung mucosa and antigen-presenting cells [74]. Apparently, COVID-19 also altered several amino acid metabolisms in infected patients. In addition to the increase of KYN level in sera, upregulation of aspartate, arginine, tyrosine, and lysine amino acid metabolites was also found elevated in the sera samples of COVID-19 patients. Several metabolites associated with arginine metabolism are also elevated, such as the release of glutamate by PBMC collected from COVID-19 patients [75]. Markedly, glutamate catabolism is found functionally unavailable [76]. Glutamate is one of the important neurotransmitters and can be associated with the neurological patterns observed in some COVID-19 patients. Collectively, elevated levels of KYN, quinolinic acid, and glutamate might have led to neuronal toxicity and hence promoted the development of neurological sequels in COVID-19 patients and survivors [77]. It can be associated with the impairment of neuronal transmission in COVID-19 patients who also have central nervous system (CNS) problems triggered by virus. During COVID-19, the KYN pathway and enzymes become activated, so that the tryptophan metabolism is altered [72, 78, 79]. Many studies have shown that an increased or highly activated KYN pathway in CNS triggers fatigue, neuronal disorders, and depression, similar to the “Long COVID-19” syndrome [80], [81], [82]. Owing to its importance in the CNS, changes in tryptophan metabolism might be associated with the Long COVID-19 syndrome in patients but needs to be studied. Indeed, some studies had found a series of selective inhibitors targeting the KYN metabolite (PF-04859989, glycyrrhizic acid, glycyrrhetinic acid, carbenoxolone, ZINC35466084) that showed marked improvement in neurological problems [83], [84], [85]. A list of chemical drugs targeting metabolism is given in the (Table 1).

Table 1:

List of chemical reagents used for metabolic control and their mechanism of action along with reported functions.

Metabolic drug Metabolic target Mechanism of action Functions Ref
2DG Glycolysis 2DG is an inhibitor of glycolysis Impair proinflammatory cell development and proposed as an antiviral against SARS-CoV-2 replication [19, 66]
Oxamate Glycolysis Inhibitor of lactate dehydrogenase enzyme Reduce the SARS-CoV-2 replication in Caco-2 cells [23]
A922500 Fatty acid metabolism Inhibitor of DGAT-1 Diminish the SARS-CoV-2 replication in monocytes [29]
Fluvastatin Cholesterol Inhibit the enzyme HMG-CoA reductase that responsible for cholesterol production Reduce SARS-CoV-2 replication in Calu-3 cells and human primary bronchial epithelial cells [34]
Mitoquinol ROS Suppressor of ROS production in mitochondria Inhibit viral replication in SARS-CoV-2 infected monocytes [23]
PF-04859989 and ZINC35466084 Tryptophan KYN type II enzyme inhibitor Reduce KYN acid level and improve neurological problems [83], [84], [85]
Metoprolol −a β-Adrenergic blockor and antagonize the lactate Significantly reduced the level of neutrophils in BAL of COVID-19 infected patients [100, 101]
Rapamycin Overall metabolic functions mTOR inhibitor Enhance virus specific memory CD8+ T cell [151]
Metformin Glycolysis, OXPHOS and FAO Activates AMPK signalling, inhibits the mitochondrial respiratory chain (complex I) and stimulates FAO Boost memory B and CD8+ T cell development [153, 154]

  1. aThe metabolic target of metoprolol is unclear but has effect on blood lactate level.

In a comprehensive metabolomic panel study, COVID-19 patients have been categorized into asymptomatic, mild, severe and deceased groups and they have found similar metabolic patterns from patients` sera in agreement with previous studies such as decreased levels determined in glutamine, arginine, tryptophan, fatty acids while kynurenic acid and several other metabolites in KYN metabolism is increased from mild to fatal cases. Additionally, study results also indicated that acylcarnitines were increased in infected patients while returned to normal values during discharge from the hospital [86]. A similar outcome was also observed in a different study [87] which is reflecting the consistency of the results addressed in this review.

Possible metabolic targets for prophylactic and therapeutic interventions

The pathogenicity of COVID-19 can be reduced by readjusting one’s diet or supplementing it with various vitamins, minerals, etc., some of which have shown promising results [88]. Moreover, an inverse relationship was observed between high C-reactive protein (an indicator of inflammation) and the level of vitamin D, person with high level of vitamin D has lower level of C-reactive protein. Patients having good vitamin D levels presented a lower level of cardiopulmonary resuscitation [89]. The poor prognosis of COVID-19 was also attributed to reduced levels of vitamin D, with deficient people displaying severe COVID-19, compared to non-deficient people [90]. However, the clinical effect of vitamin D supplementation found either no beneficial effect or demonstrated slightly better outcomes in COVID-19 patients, making the use of vitamin D supplementation in COVID-19 patients uncertain [91, 92]. Vitamin C was also considered a potential treatment option in COVID-19 cases. Intravenous vitamin C was tested on 17 severe COVID-19 patients for a trial and the study showed that vitamin C enhances the recovery of patients by reducing the levels of various inflammatory markers [93]. A meta-analysis study also collected the outcomes of daily supplementation of vitamin C and its relationship with disease severity and found from 8 trials covering 685 participants, that vitamin C reduces the rate of mechanical ventilation and shortens intensive care unit (ICU) duration in COVID-19 patients [94]. Amino acid supplements such as oral L-glutamine treatment were also tested in hospitalized patients and showed promise by reducing the hospitalization and ICU time for COVID-19 patients [95]. In terms of mineral supplementations, patients taking zinc sulfate with other medication were quicker to be discharged and had a reduced rate of being put in an ICU and mortality, compared to patients having only regular patient care without zinc treatment [96]. Using zinc supplementation in in vitro cultures also reduced the replication of SARS-CoV-2 in Vero E6 cells [97]. Conversely, a study of non-hospitalized COVID-19-positive patients administered high doses of vitamin C, zinc gluconate, or a combination of both supplementations after COVID-19 diagnosis showed no significant difference, compared to the standard of care patients regarding the progression of symptoms [98]. In other similar studies revealed no benefit from the use of dietary supplementations which are believed to improve the COVID-19 outcomes. Besides, the Center for Disease Control and Prevention has clearly stated that though some supplements increase immunity, the data are insufficient to recommend any kind of supplementation to treat or prevent COVID-19, including herbal therapies (https://ods.od.nih.gov/factsheets/COVID19-HealthProfessional/#h6).

Currently there is no clinical evidence about therapies with glycolysis inhibitors such as 2DG in COVID-19 patients. Even though in the absence of clinical study results, glucose inhibitor drug 2DG has took approval from Drug Controller General of India and Central Drugs Standard Control Organization for phase-II clinical trials to test on COVID-19 patients [99]. The use of LDHA inhibitors has not been evaluated yet in vivo but indirect serum lactate-reducing agent-metoprolol has shown a beneficial effect in COVID-19 with ARDS patients [100]. A study has shown that the intravenous administration of metoprolol improved oxygenation, and reduced inflammatory cell accumulation (especially neutrophils) in bronchoalveolar lavage, compared to untreated COVID-19 with ARDS patients [100]. However, the use of beta-blockers might have a potential anti-inflammatory therapeutic effect, which is beyond lactate reduction [101]. Metformin is the blood-glucose controlling FDA approved drug for people living with type-II diabetes. In consideration of therapeutic effect of metformin, several clinical studies and cohorts indicating that metformin lower the mortality, hospitalization and ICU admission [102], [103], [104], [105], [106]. The mechanistic explanation remain unknown but it appears that metformin acting like anti-inflammatory and immunomodulatory on immunity by reducing IL-6 and TNF-α levels, and improving the T cell response in COVID-19 patients [107, 108].

Impaired lipid metabolism took attention in people during admission even during post-COVID-19 stage. It`s also worth mentioning that low blood lipid level is found independent risk factor associated with severe COVID-19 [69]. Clinical studies on lipid lowering agents are currently limited with to statin and it`s derivatives. A study has shown that statin treatment before or during hospitalization did not reduce COVID-19 mortality significantly, compared to statin-free treatment group. However, continuous use of statins was found beneficial to reduce mortality in hospital compared to statin-free treatment group [31]. Indeed, a meta-analysis collected published data and estimated adjusted risk analysis in pooled data of clinical statin studies showing the statin use is associated with reduced risk of adverse outcomes by 36–49% in COVID-19 patients [109].

Studies also considered change of diet to reduce the burden of COVID-19. A ketogenic diet was studied and found to be beneficial for specific COVID-19 patients [110]. A study was conducted on murine beta coronavirus infection (given that it shows many symptoms similar to COVID-19) and it was observed in the aged infected that a ketogenic diet enhanced the proliferation of tissue-protective gamma delta T cells. It also reduced the levels of the NLRP3 inflammasome; moreover, the level of monocytes in the pulmonary system was also at a lower level. Besides, the levels of some pro-inflammatory cytokines and molecules (IL-1b, TNF, IL-6, NLrp3, Casp1) were reduced in the lungs, visceral adipose tissue, and hypothalamus in keto diet-fed mice [111]. A retrospective study found that COVID-19 patients on a calorie-balanced ketogenic diet have a lower rate of ICU admission and a higher rate of survival, compared to those on a calorie-balanced diet [112].

A diet rich in processed food, refined sugar, and saturated fat, often referred to as the Western diet, is associated with inflammatory adipose tissue development and immunity resembles a pro-inflammatory state, similar to chronic infection [113]. A study has investigated the impact of a Western-like diet on the severity of SARS-CoV-2 infection in hamster animal model. Results showed that hamster fed a high-fat-sugar diet showed poor lung pathology, delayed viral clearance, and prolonged viral shedding along with delayed lung recovery upon infection, compared to regular chow diet-fed hamsters [114]. A global data analysis study observed that the COVID-19-related death rate is more and the recovery rate less in populations that consume a more Western-like diet [115]. The concerns related to the Western diet include its causing adipose tissue development, obesity, and imbalance in immune response, constituting a risk factor for the increase of COVID-19 severity.

Metabolic instructions of immunometabolism after vaccination

Metabolic requirements of immune memory

Immune cells tailor their metabolic requirements in response to stimulation through cell receptors such as the T-cell receptor and B-cell receptor. Cellular signaling cascades decide the fate of immune cells by rewiring their metabolism. Naïve T cells become metabolically activated and show metabolic adaptation upon encounter with antigens [116]. Metabolically activated cells increase nutrient uptake with preference to glucose from the environment and cells enter the transition stage [117]. Consequently, subtypes of T and B cells derived from naïve cells [116, 118]. Effectively functioning immune cells rooting from naive cells will either be terminally differentiated to memory cells or die. This stage occurs when immune hemostasis establishes in the absence of cell receptor signaling or antigens [119, 120]. In a model proposed by Youngblood et al. memory CD8+ T cells shared similar patterns of epigenetic traits with effector CD8+ T cells during acute lymphocytic choriomeningitis virus infection, suggesting that memory CD8+ T cells differentiated from effector cells [121]. These findings were also demonstrated in people vaccinated against yellow fever, highlighting the memory cells ascending from effector cells rather than naïve cells [122]. Effector T cells rely mostly on glycolysis and preferentially convert glucose to lactate, rather than employ pyruvate in mitochondria, also known as aerobic glycolysis [123, 124]. There is a distinctive metabolic trait between memory type and effector cells. The differences in metabolic dynamics further affect the longevity of cells, their survival, and their functions. How naïve T cells decide to be short-living effector cells or long-living memory cells remains unknown but it is often attributed to cell-intrinsic factors upon antigen encounter, epigenetic traits, and immunometabolism [125].

The success of protection from challenging infections is judged by the longevity of the immune memory formation, as seen in measles, mumps, rubella, and herpes varicella-zoster virus (VZV) [126]. In a phase-II VZV vaccine trial, the efficacy and durability of VZV vaccination were studied in healthy older adults after two series of vaccine regimes. Results from this clinical investigation revealed that the vaccine elicited both viral protein-specific antibodies and CD4+ T cells and persisted up to 6 years after vaccination, at which antibody concentration was measured as 7.3 fold and the numbers of CD4+ T cells presented 3.8 fold higher, compared to pre-vaccination values [127]. Those studies about the metabolic state of effector and memory cells demonstrate that aerobic glycolysis is demanded by effector cells, while terminally differentiated memory cells prefer to centralize the mitochondria for survival [128]. The metabolic requirements of T cells are well characterized and it is widely accepted that memory T cell subtypes mainly utilize OXPHOS in mitochondria by fueling TCA with FAO [129].

Most notable studies have sought to understand the metabolic needs of T cells, but the metabolic states of B cells remained unexplored. Limited studies have explored the area of B cell metabolism, finding that antigenically activated B cells can also terminally differentiate into antibody-producing plasma memory B cells [130]. Another study showed that short-living plasma B cells are metabolically distinct from long-living plasma B cells [131]. Antibody-producing long-living memory B cells uptake significantly more glucose than short-living B cells to glycosylate the antibodies and fuel mitochondrial OXPHOS by pyruvate inputs, so that they maximize their survival [132]. Therefore, a successful antigen stimulation is needed to maintain an intact OXPHOS metabolism in both T and B immune cells for longer durability and protection.

Do vaccines affect people with metabolic disorders?

Obesity is considered an independent risk factor for influenza, as seen in COVID-19-associated respiratory illness [133, 134]. One of the earliest studies done with PBMC samples drained from obese people who received a flu shot showed that overweight and obese individuals had defective CD4+ and CD8+ T cells [135]. Regarding reduced levels of IFN-γ and granzyme B expression from PBMCs collected from obese individuals, it is suggested that a deficiency in T cells in adjusting their effector functions failed upon flu virus antigen stimulation [135]. Studies also indicated that flu-immunized obese mice showed poor prognosis when challenged with a live virus, compared to lean mice [136]. A study assessed the immune responses in obese persons and people with physiologically healthy weight after flu vaccination. The study failed to report a difference in terms of the antibody level between the two groups. However, results showed that obese individuals were two times more vulnerable to develop influenza and flu-like illness, compared to non-obese people, suggesting that the development of cellular immune response in obese individuals might be altered [137]. Karlsson et al. also support this idea with a study in which diet-induced obese mice showed reduced neutralizing antibody response and low levels of memory CD8+ T cells against flu immunization, compared to their healthy counterparts [138, 139].

Though limited vaccine efficacy has been observed in obese people for other many diseases, it should be highlighted that there is no clear evidence that approved COVID-19 vaccines are not effective in obese people. A clear statement was issued by The Obesity Society that all approved COVID-19 vaccines are protective and effective in people with obesity, there being no differences in this regard with non-obese individuals [140]. Arguably, we still need well-designed clinical experiments to conclude whether vaccines provide a long-lasting immune response in people with or without obesity. Besides, such people with a risk factor contributing to the development of severe COVID-19 should be prioritized for vaccination widely in all populations, without consideration of age, sex, or other risk factors.

Another special group of people at risk of developing severe COVID-19 is people with diabetes, who are also considered to develop a weak immune response against COVID-19 vaccines. Studies to understand vaccine efficacy in diabetic patients show strong efficacy against COVID-19 when results are judged by neutralizing antibody levels [141, 142]. Additionally, people who have type 1 or type 2 diabetes (T2D) showed mild or no side effects upon administration of vaccines, similar to people with no diabetes [143]. Another study investigated the effects of glycemic control after vaccination and revealed that those with good glycemic control demonstrated similar CD4+ T cell count and neutralizing titer to non-diabetic individuals, while results were significantly higher compared to poor glycemic diabetic individuals [144]. Due to increased concerns about comorbidities leading to severe COVID-19, the World Health Organization has recommended and prioritized people with comorbidities such as diabetes, obesity and cardiovascular diseases to receive COVID-19 vaccines and booster doses 4–6 months after their first vaccination [7]. However, a vaccine efficacy comparison analysis indicated that each pre-existing metabolic condition had a significantly low anti-spike receptor binding domain IgG antibody response in people who received different vaccines [145]. Nevertheless, a study investigated IFN-γ-expressing Th1 CD4+ T cells response along with neutralizing antibody levels in poor glycemic individuals, and results were accounted less when compared to good glycemic control-showing T2D patients. Additionally, the study showed that good glycemic control in T2D patients improved the immune responses after COVID-19 vaccines [146]. Another clinical study investigated the humoral immune response after COVID-19 vaccination among individuals with T2D, obesity, and hypertension as metabolic morbidities. Study results could not find significant antibody changes in people presenting hypertension and obesity and showed strong levels of antibody responses in both diabetics and nondiabetics. Even neutralizing antibodies were measured less in diabetic individuals compared to non-diabetic people; as such, there were no significant differences [147]. In line with these research findings, people with metabolic diseases must be prioritized and could maximize their immune responses by receiving a series of available vaccines.

Can we extend the efficacy of the COVID-19 vaccine by targeting immune metabolism?

Various ways have been defined to increase the efficacy of vaccines, such as improving the vaccine platform by using bioinformatics; even artificial intelligence-aided vaccine candidate platforms have been described [148]. More commonly, developing new adjuvants or changes in the vaccine delivery route was considered to boost immune memory against pathogens. A successful vaccine should elicit a strong immune response with long durability. The long durability is attributed to the establishment of memory T and B cells soon after immunization [149, 150]. Several studies have been conducted at the preclinical stage by adjusting metabolism to elicit long-living memory cells. A study showed that inhibition of the mammalian target of rapamycin (mTOR) by its target rapamycin successfully and significantly generated virus-specific memory CD8+ T cells, compared to normal vaccine recipients using both inactivated and live vaccine platforms in mice and primates respectively [151]. mTOR is known as the cellular energy sensor and its activation enhances nutrient uptake and glycolysis [152]. Using a different approach, that is the activation of AMP-activated protein kinase (AMPK) with metformin, was also shown to enhance the memory CD8+ T cells in an in vivo cancer vaccine study. This study also showed that the majority of the metformin recipients survived after tumor challenge. Activation of AMPK also acts by the suppression of mTOR, while maintaining the FAO. It was also highlighted that the activation of FAO is important for memory CD8+ T cells [153]. A study also tested the idea of metabolic treatment in flu vaccination and concluded that AMPK activation enhanced the development of memory B cells in T2D patients, even in those with obesity, compared to non-metformin users [154]. Some of these metabolic drugs are also part of the immunosuppressive group of agents. Although successful results were taken from preclinical and clinical studies, using such metabolic drugs should be considered with caution due to their immunosuppressive effects. These agents limit proliferation and reduce the inflammatory responses, while maintaining the cellular longevity. Notably, immunocompromised individuals showed less seroconversion after COVID-19 vaccination and similarly, people taking immunosuppressive drugs like autoimmune disorder patients, cancer patients, and transplant recipients demonstrated lower seroconversion after vaccination, due to immunosuppressive medications [155]. Early studies also suggested the use of metabolic therapy after vaccination to be started either during the booster immunization or when the immune response peaked. Possible ways of enhancing immunity have been described in Figure 2.

Figure 2: A possible mechanism and metabolic targets to boost memory cells after vaccination. Immune cells recognize the antigens presented by antigen-presenting cells (APC) on MHC-II and activate naïve B and T cells. Immune cells undergo clonal expansion after stimulation of phosphoinositide 3-kinase (PI3K)–AKT signaling through T cell receptor (TCR) and B cell receptors (BCR). Activated B cells produce antigen-specific antibodies and T cells become effector T cells such as producers of IL-4, IL-17, or IFN-γ cytokines. The majority of the immune cells are short-lived and they die after triggering apoptosis when TCR/BCR signaling no longer exists. Only a few long-living memory cells survive during homeostasis. The use of metabolic inhibitors or activators can induce and promote long-living and antigen-specific memory immune cells after the immune response reaches its peak [121, 122, 151, 153, 154].
Figure 2:

A possible mechanism and metabolic targets to boost memory cells after vaccination. Immune cells recognize the antigens presented by antigen-presenting cells (APC) on MHC-II and activate naïve B and T cells. Immune cells undergo clonal expansion after stimulation of phosphoinositide 3-kinase (PI3K)–AKT signaling through T cell receptor (TCR) and B cell receptors (BCR). Activated B cells produce antigen-specific antibodies and T cells become effector T cells such as producers of IL-4, IL-17, or IFN-γ cytokines. The majority of the immune cells are short-lived and they die after triggering apoptosis when TCR/BCR signaling no longer exists. Only a few long-living memory cells survive during homeostasis. The use of metabolic inhibitors or activators can induce and promote long-living and antigen-specific memory immune cells after the immune response reaches its peak [121, 122, 151, 153, 154].

Conclusions

After the outbreak of COVID-19, people with pre-existing conditions suffered more than others who are metabolically healthy. Global data increased the focus and directed the efforts to such groups to understand metabolic relationship between disease severity and susceptibility to COVID-19 infection. These outcomes were explained by the virus-altered cellular metabolism and caused metabolic impairment in the cells they infect. It has become clear that SARS-CoV-2 altered several metabolic pathways, profoundly elevated glycolysis, and led to impairment in mitochondria. Attempts at using metabolic drugs to reverse or modulate cellular metabolism during infection appeared beneficial but most of these drugs are at the preclinical stage or under clinical investigation. The use of vitamins, amino acids, and mineral supplementations or change of diet has still not been fully elucidated and remains controversial. On the other hand, pre-existing metabolic conditions such as diabetes, obesity, and cardiovascular diseases often showed poor immune responses against SARS-CoV-2 and even against COVID-19 vaccines. We suggest that targeting immunometabolism to extend long-term protection might improve the immune responses after the COVID-19 vaccine especially in people with metabolic diseases.

Corresponding author: Engin Berber, DVM, PhD, College of Veterinary Medicine, University of Tennessee, Knoxville, 37996, TN, USA, Phone: +1 (865) 249 5855, E-mail:
Engin Berber and Deepak Sumbria contributed equally to this work.

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

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Received: 2022-06-19
Accepted: 2022-08-24
Published Online: 2022-09-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. News in DMPT: Leaders in Pharmacogenetics Section
  4. Reviews
  5. Application of vibrational spectroscopy and nuclear magnetic resonance methods for drugs pharmacokinetics research
  6. A metabolic blueprint of COVID-19 and long-term vaccine efficacy
  7. Concept of Unani Jali (detergents/cleansers) drugs and its scientific validation: scope for new opportunities in dermatological pharmacotherapeutics
  8. Original Articles
  9. Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations
  10. CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women
  11. Evaluation of pharmacogenomic evidence for drugs related to ADME genes in CPIC database
  12. Therapeutic drug monitoring of teriflunomide: do plasma concentrations predict response to leflunomide in patients with rheumatoid arthritis?
  13. The investigation of the complex population-drug-drug interaction between ritonavir-boosted lopinavir and chloroquine or ivermectin using physiologically-based pharmacokinetic modeling
  14. Phytochemical investigation, antioxidant and anticancer activities of various Unani drugs
  15. The efficacy and safety of dry cupping in cervical spondylosis with optimization of cup application time – a randomized clinical trial
https://doi.org/10.1515/dmpt-2022-0148
Schlagwörter für diesen Artikel
COVID-19; immune therapy; metabolic drugs; metabolism; SARS-CoV-2; vaccination

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. News in DMPT: Leaders in Pharmacogenetics Section
  4. Reviews
  5. Application of vibrational spectroscopy and nuclear magnetic resonance methods for drugs pharmacokinetics research
  6. A metabolic blueprint of COVID-19 and long-term vaccine efficacy
  7. Concept of Unani Jali (detergents/cleansers) drugs and its scientific validation: scope for new opportunities in dermatological pharmacotherapeutics
  8. Original Articles
  9. Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations
  10. CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women
  11. Evaluation of pharmacogenomic evidence for drugs related to ADME genes in CPIC database
  12. Therapeutic drug monitoring of teriflunomide: do plasma concentrations predict response to leflunomide in patients with rheumatoid arthritis?
  13. The investigation of the complex population-drug-drug interaction between ritonavir-boosted lopinavir and chloroquine or ivermectin using physiologically-based pharmacokinetic modeling
  14. Phytochemical investigation, antioxidant and anticancer activities of various Unani drugs
  15. The efficacy and safety of dry cupping in cervical spondylosis with optimization of cup application time – a randomized clinical trial
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