Austrian Multi-Omics Study Discovers Unique Anti-Inflammatory Immune Signature And Metabolic Alterations In Individuals With Long COVID
Long COVID Research
: A new multi-omics study by researchers from the Medical University of Vienna-Austria, the University of Applied Sciences FH Campus Wien-Austria and the University of Vienna -Austria has discovered a unique anti-inflammatory immune signature and metabolic alterations in individuals with Long COVID.
The Long COVID Research
findings showed that the proportions of cytokines, oxylipins, acute phase proteins, and metabolites in blood plasma of long COVID individuals were independently predominated by anti-inflammatory mediators and devoid of proinflammatory activity but investigations strongly suggested a mostly catabolic metabolism among Long COVID individuals, possibly explaining the defining symptoms of chronic exhaustion (CFS).
Soluble tumor necrosis factor receptor II (TNF-RII), interleukin 18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1/CCL2), were considerably down-regulated among the Long COVID individuals and serpin family A member 5 (SERPINA5) levels were considerably lower. Elevated amounts of docosahexaenoic acid (DHA), its metabolites, and other docosanoids were also discovered among Long COVID patients. They also had significantly higher osmolyte taurine levels. Hypaphorine or TrpBetaine was the metabolite that was up-regulated considerably in Long COVID patients.
Despite the increasing prevalence of patients with Long COVID Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization.
In order to address these issues, the study team performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long COVID Syndrome (LCS) patients.
Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS). Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups.
Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients.
The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients.
The study findings present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.
study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.07.11.22277499v1
The study findings illustrated anti-inflammatory and hypo-metabolic fingerprints in long coronavirus disease (COVID) syndrome (LCS) using pan-omics plasma assessments.
Post-acute COVID syndrome (PACS) commonly known as Long COVID is a novel somatic illness caused by the prolonged persistence of COVID-19 symptoms following SARS-CoV-2 infection.
Typically, Long COVID patients experience generalized fatigue, poor physical fitness and concentration, postural tachycardia, dyspnea, and a wide range of other clinical symptoms, significantly reducing the quality of life.
It is expected that due to the high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection incidence globally, LCS prevalence might dramatically rise in the coming years, creating new long-term challenges for the health sector and adding to the burden of COVID-19.
However, despite the increasing number of individuals with long COVID, the pathogenesis of the condition is still unknown, making diagnosis and treatment difficult and non-standardized.
Considering the paucity of evidence regarding long COVID pathophysiological pathways, the Austrian study team decided to conduct a large-scale exploratory investigation examining the lipidome, proteome, and metabolome among LCS patients.
The study team recruited healthy individuals who had received COVID-19 vaccinations and individuals who had fully recovered from acute SARS-CoV-2 infection as control cohorts.
The study team used advanced post-genomic profiling techniques on blood plasma collected from three groups: 1) symptomatic COVID-19 patients at least three months following a SARS-CoV-2 infection, referred to as LCS patients in this study, 2) COVID-19 vaccinated healthy subjects lacking exposure to the whole virus, and 3) asymptomatic fully recovered COVID-19 patients about three months post-SARS-CoV-2 infection.
All research subjects were recruited from May to June 2021. The researchers enrolled PACS patients from the internal medicine's outpatient ward at the Medical University of Vienna, Austria. The sex and age-matched healthy/recovered and the vaccinated/healthy study cohorts were recruited among subjects following calls at the University of Applied Sciences, Vienna, Austria, and the Medical University of Vienna/Vienna General Hospital.
The study findings presented unambiguous proof of systemic anti-inflammatory conditions in PACS patients, contrary to the acute SARS-CoV-2 infection scenario. The proportions of cytokines, oxylipins, acute phase proteins, and metabolites in blood plasma were independently predominated by anti-inflammatory mediators and devoid of proinflammatory activity.
Detailed metabolomics investigations strongly suggested a mostly catabolic metabolism among LCS patients, possibly explaining the defining symptoms of chronic exhaustion (CFS).
Importantly, three indicators among the identified cytokines, chemokines, and soluble receptors: soluble tumor necrosis factor receptor II (TNF-RII), interleukin 18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1/CCL2), were considerably down-regulated among the LCS cohort. Acute-phase proteins were down-regulated in the proteome and were particularly obvious between the recovered and the LCS cohort.
Significantly, serpin family A member 5 (SERPINA5) levels were considerably lower in the LCS cohort than in the healthy and convalescent groups, revealing a distinctive characteristic of LCS.
Since the most drastically down-regulated proteins in LCS patients directly influenced macrophage activity or were derived from macrophages, the identified proteome trends imply variable macrophage/monocyte polarization and function between the LCS and the recovered cohort. Independent proof of an anti-inflammatory condition was demonstrated by the patterns seen in the lipidome of LCS patients.
The study team also discovered elevated amounts of docosahexaenoic acid (DHA), its metabolites, and other docosanoids among LCS patients.
The study findings showed a lack of inflammatory mechanisms in LCS. The PACS patients had significantly higher osmolyte taurine versus the other two groups. Hypaphorine or TrpBetaine was the metabolite that was up-regulated considerably in LCS patients.
Interestingly, in contrast, the recovered group had significantly higher levels of hypoxanthine, accompanied by other signs of tissue hypoxia as seen in acute inflammation, while LCS patients had levels more in line with the healthy group.
The detailed metabolome investigations revealed the first clues suggesting an abnormal amino acid metabolism in LCS, in addition to the overall pattern of anti-inflammation. In line with this, branched-chain amino acid levels, especially glucogenic and ketogenic amino acids, were markedly reduced in the PACS group. This finding provides evidence for higher protein breakdown-related energy consumption.
The study findings also depict the mechanisms of successful recovery following acute COVID-19. The symptom-free recovered subjects demonstrated variations in most measured metrics across the distinct biomolecular compartments relative to the healthy control cohort. These inferences showed that systemic mechanisms were still functioning in these individuals months after an acute infection. Therefore, long after symptomatic improvement, COVID-19 may still leave molecular traces, like infected macrophages.
The study findings show that the molecular patterns obtained offer initial insights into the pathophysiology of SARS-CoV-2 sequelae and also serve as a starting foundation for defining LCS-specific biomarkers. Unfortunately, the present large-scale analyses did not find a distinct and precise marker for PACS. However, numerous relevant molecular changes can be linked to the disease's recognizable symptoms.
Furthermore, the combination of currently described docosanoids (like high DHA), proteins (like low SERPINA5), and small metabolites (like high hypaphorine) among patients with characteristic anamnesis and symptoms might aid in the identification and improved definition of LCS.
Additional research is warranted to evaluate the possible sensitivity and specificity of such ratings, considering various SARS-CoV-2 strains.
The study is the first to provide evidence for a unique anti-inflammatory and highly distinctive metabolic fingerprint in long COVID, which may be beneficial for future diagnostic needs and support the development of logical treatment strategies in these patients.
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