Serotonin reduction in post-acute sequelae of viral infection

Andrea C. Wong, Ashwarya S. Devason, Iboro C. Umana, Timothy O. Cox, Lenka Dohnalová, Lev Litichevskiy, Jonathan Perla, Patrick Lundgren, Zienab Etwebi, Luke T. Izzo, Jihee Kim, Monika Tetlak, Hélène C. Descamps, Simone L. Park, Stephen Wisser, Aaron D. McKnight, Ryan D. Pardy, Junwon Kim, Niklas Blank, Shaan PatelKatharina Thum, Sydney Mason, Jean Christophe Beltra, Michaël F. Michieletto, Shin Foong Ngiow, Brittany M. Miller, Megan J. Liou, Bhoomi Madhu, Oxana Dmitrieva-Posocco, Alex S. Huber, Peter Hewins, Christopher Petucci, Candice P. Chu, Gwen Baraniecki-Zwil, Leila B. Giron, Amy E. Baxter, Allison R. Greenplate, Charlotte Kearns, Kathleen Montone, Leslie A. Litzky, Michael Feldman, Jorge Henao-Mejia, Boris Striepen, Holly Ramage, Kellie A. Jurado, Kathryn E. Wellen, Una O'Doherty, Mohamed Abdel-Mohsen, Alan L. Landay, Ali Keshavarzian, Timothy J. Henrich, Steven G. Deeks, Michael J. Peluso, Nuala J. Meyer, E. John Wherry, Benjamin A. Abramoff, Sara Cherry, Christoph A. Thaiss, Maayan Levy

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Post-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

Original languageEnglish (US)
Pages (from-to)4851-4867.e20
JournalCell
Volume186
Issue number22
DOIs
StatePublished - Oct 26 2023
Externally publishedYes

Keywords

  • Long COVID
  • neurocognitive symptoms
  • PASC
  • platelets
  • post-viral syndromes
  • serotonin
  • thrombocytopenia
  • type I interferons
  • vagus nerve
  • viral persistence

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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