A dysregulated immune system and persisting inflammation could be one of the key drivers of long-term COVID-19 syndrome (LTCS)

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A new study by German researchers have found that that dysregulated metabolism and Inflammation contributes to many ongoing symptoms found in individuals with Long COVID.

The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2023.01.13.523998v1

LTCS is a condition which is thought to debilitate a person’s life after a SARS-CoV-2 viral infection and post-recovery for several months up to years. It is estimated that approximately 20-30% of all COVID-19 patients are susceptible to develop LTCS.

Through our integrative metabolomics/lipoproteins and inflammation, in this finding, we identified several metabolites and lipoprotein and cytokines which are dysregulated in LTCS patient compared with either HC, Recov or acute COVID-19 patients (Fig. 5). Our major findings revealed that lactate and pyruvate were highly upregulated in LTCS patients compared with HC and similar metabolites were also upregulated in Recov patients.

This could be due to dysregulated oxidative phosphorylation in Recov or LTCS patients. Furthermore, phenylalanine, glycine, acetate, Gln/Glu ratio, glutamine, and creatinine were downregulated in LTCS patients compared with HC or Recov which may be indicative of the LTCS symptom.

A sign of a greater long COVID-related severity state could be demonstrated by phenylalanine, ketone bodies (acetoacetate, acetone, and 3-hydroxybutyrate), formate, creatine, and pyruvate blood levels (Fig. 5). As there is a demand for the amino acid and its further pathway products, phenylalanine levels go down in COVID recovery phase patients as reported in [58], similarly to currently investigated LTCS group versus convalescent comparison.

In here, a slight change of acetoacetate could be an indicator of dietary habits changes [59] or in combination with other statistically significant parameters could predict COVID-19 disease severity [60]. From the correlational analysis, we were able to determine that correlations of creatine, glutamine, lysine, and 3-HB were stronger to the cytokine data in the LTCS group.

As they had been previously reported for COVID-19-positive patients [31; 58; 61], these metabolites can provide an insight which metabolic shifts could be persisting and represent a continuous risk to the patients’ health.

Fig. 5 Graphical summary of the study. Sub-plot (a) focuses on phenylalanine, formate, and ketone bodies (mainly, 3-hydroxybutyrate) as significant variables identified via regression model analysis. Sub-plot (b) demonstrates further strong metabolite correlations with the cytokine data. Sub-plot (c) is showing highlights of the lipoprotein data analysis.

Recov and LTCS patients showed very similar types of metabolic dysregulations. We identified some difference between the groups especially for the formate, acetate, creatinine, HDL-4 triglycerides and HDL-4 Apo-A1 apolipoprotein levels, however no significance level was achieved.

Further, we investigated a correlation between groups of Recov and LTCS. The findings therefore suggest a contrastingly higher role of creatine to IL-1b, INF-g, TNF-a (predominantly), IL-8/10/18 cytokines positive correlations among the LTCS individuals. However, our finding is similar to the previously reported association of mild/acute COVID-19 patients metabolomic analysis and its classification to the cytokine panel data [10].

Moreover, we also identified a LTCS-specific positive correlation between HDL phospholipids and IL-1b, INF-g, IL-6, IL-12p70, IL-23/33. This evidence could be complemented with finding of HDL phospholipids among other NMR-defined lipoprotein variables in COVID-19 patients [33].

We further identified an elevation of citrate and pyruvate in blood of the LTCS patient group compared with HC. This is in line with another study which identified higher levels of pyruvic acid are accumulated in the bloodstream of COVID-19 patients and which could be used to prognose disease severity [62].

Further, greater levels of lactate in COVID-19 patients are an already established finding [63]. We therefore speculate that glycolysis/gluconeogenesis and Krebs cycle metabolic pathways will lead to the elevated consumption of glucose to produce citric acid into the blood plasma.

It is interesting to note that the citrate levels did not significantly correlate to any of the chemokine or cytokines as yet it was only connected to the gender factor. Therefore, gender based metabolic dysregulation could play an important role to understand the disease severity. This is especially important as certain LTCS symptoms have been reported more for female or male patients.

Maintained triglycerides and other lipoproteins changes indicate that COVID-19 like features still exist in LTCS patients when comparisons were made with HC. Elevated apolipoproteins ratio B100 to A1 and overall blood triglycerides could be attributed to the disease group [49].

Although, in our study, only triglycerides showed negative correlations to IFN-a2, IL-17A, and IL-23. IFN-is connected to the innate inflammatory reaction and this could portray the ongoing need of LTCS patients to lower down SARS-CoV-2 induced dysregulation of innate immune system [64].

Our findings are prompting to speculate that a core change in cytokine levels as well as high number of triglycerides were in present in the bloodstream of LTCS patients.

This could be result of dysregulated innate immune response which could lead to a higher severity of COVID-19 like symptoms.

In a similar context of lipid levels, an increase of COVID-19 severity is increased with diabetes and as a result of lowered amounts of HDL cholesterol in COVID-19 patients [65]. Our data implies that HDL cholesterol (HDCH) is lowered in the LTCS together with correlating INF-g, IL-6, and IL-23.

Previously, it was identified that severe immunosuppression is key for the severity of COVID-19 rather than the cytokine storm [66]. Thus, it is plausible that lower level of lipids and inflammatory cytokines may be important for further disease symptoms in LTCS patients.

Another likeliness of the LTCS group to acute COVID-19 patients is noticed via lowered apolipoproteins A1 & A2 levels, among other close structures they had been lowered in ill subjects [67; 68].


Lipids are crucial in the infection process, as they are important structural components of cellular and subcellular organellar membranes. Membrane lipid components participate in the regulation of transmembrane molecular trafficking, including infectious materials such as viruses. Viral internalization requires the attachment of the virus to the host cell membrane, activating an endocytosis mechanism 5.

The membrane lipid composition and particularly the lipid rafts influence this process6. Once inside the cell, the virus replicates using the metabolic machinery of the invaded cell 7. The newly synthesized viral particles exit the cells again by crossing the lipid-rich cell membrane. Based on studies of animal models, intracellular cholesterol may increase cellular SARS-CoV-2 infectivity 8.

Recently, the SREBP-2 C-terminal fragment discovered in blood samples from patients with COVID-19 was identified as an indicator of the severity of the diagnosis and a therapeutic target for preventing the cytokine storm and organ damage 9. In the host cell, the virus modifies cellular metabolism by altering energy production pathways for its own benefit.

Both cellular glucose and lipid metabolism are extensively modified6, and a recent metabolomic study of patients infected with SARS-CoV-2 has described a specific lipidomic fingerprint10.

In addition to structural and energy supply functions, intracellular lipids also act as intracellular signalling molecules or transcription factors. Viral particles also interfere with these pathways, altering cell physiology and leading to apoptosis and cell death5.

The standard clinical approach to assessing alterations in lipid metabolism is based on the measurement of cholesterol in several lipoprotein particles and triglyceride levels. Researchers have not determined how these parameters will improve our understanding of the important role of cellular lipids in viral infections.

Infectious diseases are usually associated with low HDL cholesterol (HDL-C) concentrations and sometimes with low LDL cholesterol (LDL-C) concentrations, while triglyceride levels are typically maintained or even increased 6, 11. Low HDL-C levels have been proposed as a risk biomarker for different infections 12.

Regarding the SARS-CoV-2 infection, low LDL-C, HDL-C and triglyceride (TG) levels have been described to be associated with an increasing infection severity 6, and a role for these lipids in immune mechanisms has been suggested 13. Low lipid levels during the infection have been associated with the severity of COVID-19 14.

Meanwhile, low plasma lipid concentrations are regarded as a consequence of the hypermetabolic state and undernutrition in the infected patient; however, many metabolic pathways associated with the immune response and infection itself participate in these alterations 11.

Cytokines, inflammatory mediators, modified lipids and intermediate lipid classes generated during the infection interfere with several steps of lipid metabolism by reducing cholesterol synthesis and absorption, decreasing triglyceride-rich lipoprotein clearance or reducing apolipoprotein (apo) A1 synthesis 15.

Taken together, we hypothesise that an analysis of lipid metabolism should be contemplated as another clinical tool to evaluate the SARS-CoV-2 infection state and prognosis. Thus, the present study aimed to determine the variation in the lipid profile due to COVID-19 and its association with disease severity.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010012/

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