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.
Original reference: Cell https://doi.org/10.1016/j.cell.2023.09.013 (2023)
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