COVID-19 Research By German Scientists Shows That SARS-Cov-2 Paralyzes Cytotoxic And Metabolic Functions Of Immune Cells

COVID-19 research by German scientists from the University of Tuebingen shows that the SARS-CoV-2 coronavirus basically paralyzes the cytotoxic and metabolic functions of the human host immune cells which leads to disease severity and progression.


 
The study findings are published on a preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.09.04.282780v1
 
Till this study, it was still unclear how the SARS-CoV-2 virus interferes with immune cell and metabolic functions in the human body.
 
The study team investigated the immune response in 10 acute or convalescent COVID19 patients. They characterized the peripheral blood mononuclear cells (PBMCs) using flow cytometry and found that CD8+ T cells were significantly subsided in moderate COVID-19 and convalescent patients.
 
Significantly, characterization of CD8+ T cells suggested that patients with a mild and moderate course of the COVID-19 disease and convalescent patients have significantly diminished expression of both perforin and granzyme B in CD8+ T cells.
 
Utilizing 1H-NMR spectroscopy, the study team characterized the metabolic status of their autologous PBMCs.
 
The team found that fructose, lactate and taurine levels were elevated in infected (mild and moderate) patients compared with control and convalescent patients. Glucose, glutamate, formate and acetate levels were attenuated in COVID-19 (mild and moderate) patients.
 
The study findings reveal patients who suffer from an over activation of the immune system, a change of composition in infusion/intravenous fluids during infection with the aim to lower blood levels of glucose, glutamate, acetate and formate could avoid a life-threatening cytokine storm.
 
Recent reports from COVID-19 patients suggested that mild and severe patient had lymphopenia. The team found that mild patients have reduced lymphocyte numbers whereas convalescent patients have recovered the total lymphocyte counts.
 
Monocytes were also reduced in mild patients, which is in agreement with other recent studies. https://www.medrxiv.org/content/10.1101/2020.03.24.20042655v1
 
Importantly, the characterization of myeloid cell compartment based on CD16 and CD14 markers suggested that non-classical and intermediate monocytes were increased during an active mild or moderate SARS-CoV-2 293 infection, once infections are cleared the monocyte numbers return to normal.
 
In the cohort, specifically CD56+NK cells were dramatically decreased during the course of active SARS-CoV-2 viral infections (mild and moderate), while during recovery the numbers were comparable to HC.
 
Another recent study suggested the decrease in number of NK cell subsets in COVID-19 patients, with no change in CD56bright or CD56dim cells. Thus, these data point to a crucial role of CD56+NK cells in eliminating SARS302 CoV-2 infections. https://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32826343
 
CD19+ B lymphocytes were increased during the course of infection and remain slightly higher than HC, thus reflecting the antibody response against the COVID-19 virus. Thus, this data implicated that these patients were able to generate the SARS-CoV-2 specific B cells.
 
However, a major difference was found in the T lymphocytes compartment. On the one hand, CD4+ T cells were increased during infection, but not dramatically. On the other hand, CD8+ T cells were significantly decreased in moderate and convalescent patients as reported earlier. Thus, it appears that during viral infection non-virus specific CD8+ T cells are dead, while the viral-specific surviving CD8+ T cells are clonally expanded but appeared to lost their effector functions.
 
In order to confirm this, the team first measured the activation status of CD8+ T cells and found that CD8+ T appeared to be less activated based on their HLA-DR activation marker.
 
Further, CD8+ T cells were examined for another activation marker CD38 which is involved in cell adhesion, signal transduction and calcium signaling and was found to be upregulated in convalescent patients but not during active infection. These CD38+CD8+ T cells, were also expressing higher levels of PD-1, which is an immune checkpoint and marker of exhaustion. It guards against autoimmunity, promotes apoptosis of antigen-specific T cells and promotes self-tolerance by suppressing T cell inflammatory activity.
 
Hence, viral infection leaves convalescent patients with exhausted phenotypes. The team found that although there was not a significant change in the numbers of Tregs in COVID-19 patients, there was a trend towards elevated levels of Tregs in COVID-19 patients and rescued Tregs in convalescent patients.
 
A key finding of the study was the surprising observation that granzyme B and perforin secreting CD8+ T cells were significantly reduced in convalescent patients. The possible implication of the finding is that convalescent patients, specifically including cancer patients under treatment, could be susceptible to future opportunistic infections with other viruses including different strains of SARS-CoV-2.
 
Also it is clear that PBMCs are dependent on circulating nutrients and hormones in the blood system. The defective immune response in COVID-19 patients prompted us to investigate the metabolic functions of these immune cells.
 
The metabolomics data indeed shows that PBMCs from actively infected patients have a distinct metabolic profile from convalescent or healthy individuals. The most notable difference the team observed were for metabolites from the glycolysis and oxidative phosphorylation (TCA cycle) pathway, which is in accordance with recently published transcriptome data for PBMCs. https://www.frontiersin.org/articles/10.3389/fimmu.2017.01311/full and https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1747363
 
Metabolites such as glucose, formate, acetate and choline were also reduced in PBMCs in infected patients whereas; HC and convalescent patients had a normal profile.
 
Accordingly, the glycolytic pathway end products such as lactate were higher in active mild and moderate COVID-19 patients compared with HC and convalescent individuals. Therefore, our data suggests that PBMCs (which constitute a major fraction of T lymphoid cells: 70- 80%) may have changed their metabolic functions, particularly favoring the oxidative phosphorylation pathway over the glycolytic pathway, to meet the high demands of energy needed to combat the ongoing viral infection.
 
A recent report suggested that elevated glucose levels enhance SARS-CoV-2 replication and cytokine expression in monocytes and glycolysis sustains the viral-induced monocyte response. https://www.sciencedirect.com/science/article/pii/S155041312030365X
 
Recently, it was emphasized that glucose consumption in PBMCs during COVID350 19 disease could be also a read-out of cytokine storms. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01636/full
 
Further, a higher abundance of citrate in PBMCs suggested that perhaps T cells could use the oxidative phosphorylation pathway for energy consumption to endure the infection, as recent transcriptomic data also suggested that higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and bronchoalveolar lavage fluid (BALF) could play a crucial role in increased mitochondrial activity during SARS-CoV-2 infection.
 
Another interesting study finding was the increase of fructose levels in PBMCs during the course of infection.
 
Previous findings suggested that fructose is involved in the inflammatory pathways for the production of IL-1β and IL-6 production6. Thus, it is possible that the immune cells (most probably monocytes) could be triggered by higher fructose and simultaneously induces inflammation and IFN-γ production by T cells. https://pubmed.ncbi.nlm.nih.gov/30919933/
 
These findings are correlating with recent transcriptomic studies on the BALF from infected COVID-19 patients and plasma of COVID-19 patients that also identified changes in fructose metabolism.
 
The team also observed a reduction of granzyme B and perforin in CD8+ T cells and detected the antioxidant amino acid taurine, which could be involved in the cytotoxic functions of CD8+ T cells. Both granzyme B and perforin are involved in ROS production and taurine serves as ROS scavenger63,64.
 
Hence, decreased granzyme B and perforin could be implicated in reduced ROS production for the impaired effectiveness of CD8+ T cells in convalescent or COVID-19 patients. This should be the case, as taurine levels that are generally increased during an active infection in mild patients compared to healthy controls are not specifically decreasing due to granzyme B and perforin lacking ROS activity in COVID-19 patients.
 
However, this finding needs further investigation to validate this hypothesis.
 
 In summary, the metabolomics data generated in this study provides first and crucial insights into the complex metabolic changes of PBMCs during SARS-CoV-2 infections, warranting further investigation.
 
The dramatic changed metabolic activity and pathways, such as glycolysis and TCA cycle, might not only lead to a vulnerability of COVID-19 patients to subsequent infections, but can also offer insights into how PBMCs could be manipulated towards a better survival and personalized treatment of moderate and severe COVID-19 patients.
 
In summary, the study report suggests that SARS-CoV-2 infection leads to disrupted CD8+ T cytotoxic functions and changes the overall metabolic functions of immune cells.
 
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