Histamine signalling evolution
Histamine

covid and taurine

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC), 2022

• Abstract
  Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan—a hallmark of disease severity in COVID-19—is not normalized in PASC patients, despite normalization of kynurenine levels—a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

IFN response depletes serotonin, 2023

• The molecular etiology of long COVID remains unclear. In Cell, Wong et al. find that acute and chronic viral infection in mice and humans cause an interferon (IFN)-dependent reduction of plasma levels of the neurotransmitter serotonin, and this could be linked in mice to memory loss and vagus nerve dysfunction. Based on plasma metabolomics in 58 individuals with long COVID (up to 22 months after acute infection), serotonin reduction shows the strongest correlation with symptom persistence. Serotonin is reduced in humans and mice with acute SARS-CoV-2 and non-SARS-CoV-2 viral infection, in mice injected with the synthetic double-stranded RNA poly(I:C), and in mice with chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infection, but not in mice that lack Ifnar, Tlr3 or Stat1. Treatment with poly(I:C) and SARS-CoV-2 infection induce the IFN-dependent downregulation of genes encoding amino acid transporters (Slc6a14 and Slc7a19) and chaperones (Ace2) in the small intestine in mice and in human organoids, and prevent tryptophan absorption. Mice infected with vesicular stomatitis virus (VSV) and LCMV clone 13 have reduced numbers of platelets, which are known to transport serotonin, and increased expression of the MOA enzyme, which degrades free plasma serotonin, and show decreased recognition of novel objects, which is rescued by TLR3 deletion or tryptophan restauration. Virus-infected mice have normal levels of serotonin in the brain but reduced sensory neuron activity in the brain stem in response to novelty exposure. Stimulation of PHOX2B+ vagus nerve neurons, restoration of plasma serotonin with the serotonin precursor 5-HTP, or treatment with an agonist for the serotonin receptor 5-HT3, which is expressed by the vagal neurons, restores short-term memory formation in poly(I:C)-treated mice. These observations link the reduction of serotonin to the cognitive symptoms reported by individuals with long COVID.