Immunometabolism is the intersection of immunology and metabolism, where immune cells use metabolic pathways to generate energy and support their functions. It is now recognized that metabolic processes are essential for proper immune function, and metabolic dysregulation can lead to immune dysfunction.
Studies have shown that SARS-CoV-2 infection affects the human immunometabolism by altering the metabolic pathways of immune cells. For example, one study found that SARS-CoV-2 infection leads to an increase in the glycolytic activity of monocytes, a type of immune cell that plays a critical role in the innate immune response.
This increase in glycolysis was associated with the production of pro-inflammatory cytokines, which can contribute to the cytokine storm observed in severe cases of COVID-19.
Another study found that SARS-CoV-2 infection leads to changes in the metabolic pathways of T cells, a type of immune cell that plays a critical role in the adaptive immune response. Specifically, the study found that SARS-CoV-2 infection leads to a decrease in the expression of genes involved in oxidative phosphorylation, a process by which cells generate energy from glucose.
In addition to altering the metabolic pathways of immune cells, SARS-CoV-2 infection also affects the metabolism of other tissues in the body. For example, studies have shown that SARS-CoV-2 infection leads to an increase in the production of ketone bodies, which are produced by the liver during periods of fasting or low carbohydrate intake. This increase in ketone production is thought to be a response to the increased energy demand of the immune system during infection.
SARS-CoV-2 infection also affects the metabolism of adipose tissue, which plays a critical role in the regulation of energy balance and inflammation. Studies have shown that SARS-CoV-2 infection leads to an increase in the expression of genes involved in lipolysis, the breakdown of stored fat for energy. This increase in lipolysis is thought to contribute to the hyperinflammatory response observed in severe cases of COVID-19.
The effects of SARS-CoV-2 infection on the human immunometabolism have significant implications for the treatment of COVID-19. For example, targeting the metabolic pathways of immune cells could be a novel therapeutic approach to modulate the immune response and prevent severe disease. Additionally, the metabolic changes observed in response to SARS-CoV-2 infection could be used as biomarkers to predict disease severity and monitor disease progression.
A new study by researchers from University of Zacatecas-Mexico, Instituto Mexicano del Seguro Social-Mexico, Waters Technologies of Brazil, Waters Corporation-Mexico and University of Monterrey-Mexico has found that up to 170 metabolic dysregulations were found in recovered SARS-CoV-2 patients after two years.
The study findings were published in the peer reviewed journal: Frontiers In Biomolecular Sciences.
https://www.frontiersin.org/articles/10.3389/fmolb.2023.1100486/full
This study aimed at describing clinical and metabolic alterations persisting two years after patients had a SARS-CoV-2 infection of different severity. The metabolic pathways dysregulated during infection and after two years of recovery were identified.
A functional analysis approach was used assuming that putative annotation at individual compound level can collectively predict changes at functional levels, as demonstrated by Li et al. (Li et al., 2013).
Lipid classes belonging to sterols, steroids, and fatty esters were dysregulated in both COVID-19 groups studied. Very recently, Guntur et al. (Guntur et al., 2022) found higher levels of poly and highly unsaturated fatty acids in patients with post-COVID-19 syndrome (more than 28 days after infection: recruitment phase done in a time-interval of two years).
This finding was consistent with a reduced fatty acid oxidation at mitochondrial level. The accumulation of such molecules has been associated with erythrocyte dysfunction and impairment of oxygen transportation that could persist for months, thereby explaining symptoms such as fatigue and exercise intolerance.
Sterols are a subgroup of steroids. The most familiar type is cholesterol, which is vital for the membrane structure, and it is a precursor of fat-soluble vitamins and steroid hormones. A recent systematic review and meta-analysis demonstrated that lower concentrations of total HDL, and LDL-cholesterol were significantly associated with COVID-19 severity and mortality suggesting that cholesterol concentrations might be useful for risk stratification and monitoring (Zinellu et al., 2021). Ghini et al. (Ghini et al., 2022) recently demonstrated that the lipoproteome of recovered patients slowly reverted to the healthy state.
Corticosteroids such as dexamethasone belong to steroids. They have significant anti-inflammatory and anti-fibrotic effects, which may play a role reducing lung and systemic inflammation, especially in severe pneumonia and in advanced stages of COVID-19 (Leistner et al., 2022).
Among fatty esters, monoacylglycerols, diacylglycerols, and in particular, triacylglycerols, have also been associated with metabolic dysregulation in COVID-19 patients (Masana et al., 2021).
In COVID-19 patients bile acid was also found dysregulated. Bile acids are signaling molecules with immune, metabolic, and intestinal microbiota control actions (Wahlström et al., 2016). Bile acids pathways have been widely reported in COVID-19 due to the proven association between gut dysbiosis and inflammatory processes that lead to severe disease.
However, anomalies in bile acids metabolism are also associated with liver injury, and affect the substance transport system (cholesterol transport), which is common in severe COVID-19 (Shen et al., 2020). A disordered metabolism of bile acids among recovered COVID-19 patients (three months after discharge) has been documented, suggesting that the intestinal equilibrium at mucosal level is delayed before is fully repaired (Zhang et al., 2021).
In post-COVID-19 patients, the isoprenoids pathway, also recognized as mevalonate pathway (MVP) or HMG-CoA reductase pathway, was also dysregulated. Isoprenoids are a highly diverse class of biomolecules, ranging from cholesterol, vitamin K, coenzyme Q10, all steroids hormones (Holstein and Hohl, 2004). The MVP limits the activation of inflammasomes and cytokine release, and for this reason, unbalanced signaling could be associated with the pathobiology of COVID-19.
A recent in silico study revealed dysregulation of genes involved in the MVP in SARS-CoV-2 infection, but not with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus (Gomez Marti et al., 2021). Finally, the use of statins, namely, HMG-CoA-reductase inhibitors, frequently used as therapeutic agents, reduce cholesterol levels lowering viral titers through immunomodulatory, anti-inflammatory and anti-thrombotic effects (Proto et al., 2021).
These previously described metabolic alterations could account for the plethora of symptoms reported in this study. In recovered patients, values of hemoglobin, lymphocytes, monocytes, neutrophils, and creatine were within normal range two years after the acute infection. Only three out of 22 patients had one reinfection (with the Omicron variant, January 2022).
By the moment of the follow-up laboratory tests, all patients tested negative for SARS-CoV-2. However, the heterogeneity of persistent symptomatology indicates that multiple organ systems were affected during the recovery phase. The etiologies of the reported conditions are post-acute COVID-19 cardiovascular syndrome, post-acute COVID-19 neuropsychiatric syndrome, and multi-system syndrome.
In the cohort of patients with baseline and follow-up CT scans, interstitial thickening, ground glass opacity, and subpleural bands were the most frequent sequelae observed. Ground glass opacity, interstitial thickening, parenchymal bands, bronchiectasis, lymphadenopathy, and pleural effusion has been reported (Yu et al., 2020).
A systematic review and meta-analysis of 15 studies including over 3000 patient’s follow-up CT scans at 1–6 months after discharge showed residual CT changes in 55.7% of the cases (So et al., 2021). It could be possible that these anomalies could be reverted two years after infection in the absence of other lung diseases.
Remarkably, fatigue was the predominant alteration reported (59%), as well as musculoskeletal symptoms such as arthralgias and myalgias. Therefore, measuring the plasma lipid profile was relevant, as lipids plays an essential role in energy metabolism.
When the lipid profile was analyzed, multivariate analysis showed that after two years of recovery, post-COVID-19 patients cannot be grouped with negative controls neither clustered with COVID-19 patients, even though most basic laboratory parameters are normalized; yet, the presence of a wide spectrum of symptoms reflects that metabolic mediators are not reestablished at all.
Alterations in lipids have been found in recovered patients from SARS (2003). Wu et al. followed 25 recovered SARS patients 12 years after infection. The authors found increased levels of phosphatidylinositol and lysophosphatidylinositol (Wu et al., 2017).
In SARS-CoV-2, lipid metabolism has been reported altered in all the stages of the disease (Sun et al., 2020) and in the recovery phase. Our group has reported alteration in the levels of acylcarnitines and glycerophospholipids (phosphatidylcholines and lysophosphatidylcholines) upon admission in emergency rooms (early onset of symptoms) (López-Hernández et al., 2021).
Chen and cols (Chen et al., 2022). reported that in COVID-19 patients with nucleic acid turning negative (still hospitalized), lipid metabolism was dysregulated. Acosta-Ampudia et al. also found that approximately two months after discharge, the phenotype of recovered patients did not return to a similar phenotype of pre-pandemic controls, and altered levels of unsaturated fatty acids, such as arachidonic and linoleic acid were seen (Acosta-Ampudia et al., 2021). Li et al. (Li et al., 2022) found that metabolic disturbance of lipids was associated with long-term chronic discomfort and immune dysregulation in COVID-19 survivors 6 months after discharge. The authors also reported dysregulated levels of TG, LTB4, PGE2, polyunsaturated fatty acids, including 5-hydroxyeicosatetraenoic acid (5-HETE), 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-oxoeicosatetraenoic acid (15-oxoETE).
In this study, increased levels of several lipids (e.g., glycerophospholipids and sphingolipids) in the plasma of recovered patients were observed. Despite not identifying all the features dysregulated, we were able to identify (confidence level 2) the most important lipids contributing to the differentiation.
Phosphatidylcholines have been found altered in COVID-19 patients with mixed results. This is because the pattern of lipid regulation in COVID-19 patients depends upon the infection severity (asymptomatic, mild, or severe) (Hao et al., 2021). However, in most of the studies published so far, some lipid species (even within the same family) are upregulated and others downregulated, revealing a complex regulation in the context of various concomitant factors playing a role, such as the patient´s immune status and the presence of comorbidities.
Here, some species of PCs were found to decrease during the active phase of the disease, and two years later these species increased in post-COVID-19 patients, even in comparison with negative controls. This could be explained as: 1) a compensatory mechanism, 2) the persistence of molecular mechanisms that are still dysregulating lipid homeostasis, and as 3) the cross-talking with the immune system and gut microbiota.
In our research conducted in 2020 (Herrera-Van Oostdam et al., 2021), we observed a positive correlation between PCs and SMs with IL-12p70 and IFN-λ1. In line with this, a recent work has reported that patients with long COVID showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained high after 8 months of infection (Phetsouphanh et al., 2022).
On the other hand, the observed dysregulation could be due to lifestyle changes since it has been observed that mitochondrial dysfunction affect the mechanisms generating energy. Either abnormally high, or abnormally low, phospholipids can influence energy metabolism, and have large implications on general metabolic parameters (van der Veen et al., 2017).
Sphingolipids (SLs) also represent an important group of bioactive molecules involved in crucial processes such as inflammation, cellular differentiation, regeneration, aging, among others, particularly important in musculoskeletal cells (Meacci et al., 2022). The results of this study showed a dysregulation in sphingolipid metabolism, that could be associated with the reported symptoms: fatigue and muscular pain.
It has been previously observed that sphingolipids impairment affect skeletal muscle cells (Danieli-Betto et al., 2005; Cowart, 2010). Accumulation of sphingolipids has been associated with inflammatory processes, and mass decrease of skeletal muscle cells of aged mice (Trayssac et al., 2018).
Also, inactivity or disuse of musculoskeletal cells, as seen after disabled conditions, correlate well with remodeling of membranes enriched in SL and cholesterol along with changes in ceramide contents (Petrov et al., 2019). Ceramides and Hexocylceramides, which are derivatives of sphingomyelins, have been found increased in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and among those with chronic hepatitis C infection and autoimmune disease (Zhang et al., 2016; Filippatou et al., 2021).
Increased sphingolipids levels have also been observed in metabolic syndrome (Chavez and Summers, 2012) and in the acute cell danger response (Naviaux, 2014). Regarding ME/CFS, a general agreement is that metabolic features are consistent with a hypometabolic state, characterized by a decrease in sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid, and branch chain amino acid. In this study, an increase in sphingolipids and phosphocholines was observed, so an underlying mechanism like ME/CFS unlikely explains the fatigue and muscular alterations seen.
Li et al. (Li et al., 2022) found that total levels of LysoPC, PA, PC, PE, PS and Cer were significantly downregulated in elderly survivors after a maximum of 9 months of a mild disease. This difference may be explained by the type of patients studied; in that study only mild disease was included, and patients were stratified by age; and the time after the acute disease was shorter.
Summarizing, our results show that post-COVID-19 is a relevant entity that requires further research.
Results also show that after two years of SARS-CoV-2 infection, some metabolic pathways are not normalized. It was worth noting that some lipid species were downregulated in post-COVID patients, while others were upregulated even within the same lipid family. These lipid dysregulations could explain some of the persistent symptoms reported by patients, especially those related to musculoskeletal disorders. Targeted studies reporting absolute concentrations for these markers are needed to establish the precise molecular mechanisms involved, and most importantly, to eventually design potential therapeutic interventions.
Finally, some important limitations ought to be acknowledged. The sample size was small due to the exploratory nature of this study; this is the result of focus given to the recruitment of patients that previously participated in protocols approved in 2020 (first epidemic wave). As a result, after two years, nearly one-third of the patients had died at hospitals within the following months after the infection.
Also, from the patients that agreed to participate, there was limited data on the type and dosage of the medications prescribed during the recovery phase to be considered when interpreting the results. There was also lack of data regarding the occurrence of new illnesses and/or the reactivation of latent ones that could have affected the lipidomic profile of the patients.
All participating patients included in this study were sent to specialists to receive medical assistance for treating persistent symptoms.
