Metabolic reprograming shapes neutrophil functions in severe COVID-19.

To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2, we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase, and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus, suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies.

Glycogen storage disease type VI: clinical course and molecular background.

Glycogen storage disease type VI (GSD-VI; also known as Hers disease, liver phosphorylase deficiency) is caused by mutations in the gene coding for glycogen phosphorylase (PYGL) leading to a defect in the degradation of glycogen. Since there are only about 40 patients described in literature, our knowledge about the course of the disease is limited. In order to evaluate the long-term outcome of patients with GSD-VI, an observational retrospective case study of six patients was performed at the University Children's Hospital Zurich. The introduction of small, frequent meals as well as cornstarch has led to normal growth in all patients and to normalization of liver transaminases in most patients. After starting the dietary regimen, there were no signs of hypoglycemia. However, three of six patients showed persistent elevation of triglycerides. Further, we identified four novel pathogenic PYGL mutations and describe here their highly variable impact on phosphorylase function.Conclusions: After establishing the diagnosis, dietary treatment led to metabolic stability and to prevention of hypoglycemia. Molecular genetics added important information for the understanding of the clinical variability in this disease. While outcome was overall excellent in all patients, half of the patients showed persistent hypertriglyceridemia even after initiating treatment.What is Known:• Glycogen storage disease type VI (GSD-VI) is a metabolic disorder causing a defect in glycogen degradation. Dietary treatment normally leads to metabolic stability and prevention of hypoglycemia.• However, our knowledge about the natural course of patients with GSD-VI is limited.What is New:• While outcome was overall excellent in all patients, half of the patients showed persistent hypertriglyceridemia even after initiating treatment.• Molecular genetics added important information for the understanding of the clinical variability in this disease.