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 Patel; Katharina 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

doi:10.1016/j.cell.2023.09.013

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 journal › Article › peer-review

138 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 language	English (US)
Pages (from-to)	4851-4867.e20
Journal	Cell
Volume	186
Issue number	22
DOIs	https://doi.org/10.1016/j.cell.2023.09.013
State	Published - Oct 26 2023
Externally published	Yes

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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10.1016/j.cell.2023.09.013

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Wong, A. C., Devason, A. S., Umana, I. C., Cox, T. O., Dohnalová, L., Litichevskiy, L., Perla, J., Lundgren, P., Etwebi, Z., Izzo, L. T., Kim, J., Tetlak, M., Descamps, H. C., Park, S. L., Wisser, S., McKnight, A. D., Pardy, R. D., Kim, J., Blank, N., ... Levy, M. (2023). Serotonin reduction in post-acute sequelae of viral infection. Cell, 186(22), 4851-4867.e20. https://doi.org/10.1016/j.cell.2023.09.013

Wong, AC, Devason, AS, Umana, IC, Cox, TO, Dohnalová, L, Litichevskiy, L, Perla, J, Lundgren, P, Etwebi, Z, Izzo, LT, Kim, J, Tetlak, M, Descamps, HC, Park, SL, Wisser, S, McKnight, AD, Pardy, RD, Kim, J, Blank, N, Patel, S, Thum, K, Mason, S, Beltra, JC, Michieletto, MF, Ngiow, SF, Miller, BM, Liou, MJ, Madhu, B, Dmitrieva-Posocco, O, Huber, AS, Hewins, P, Petucci, C, Chu, CP, Baraniecki-Zwil, G, Giron, LB, Baxter, AE, Greenplate, AR, Kearns, C, Montone, K, Litzky, LA, Feldman, M, Henao-Mejia, J, Striepen, B, Ramage, H, Jurado, KA, Wellen, KE, O'Doherty, U, Abdel-Mohsen, M, Landay, AL, Keshavarzian, A, Henrich, TJ, Deeks, SG, Peluso, MJ, Meyer, NJ, Wherry, EJ, Abramoff, BA, Cherry, S, Thaiss, CA & Levy, M 2023, 'Serotonin reduction in post-acute sequelae of viral infection', Cell, vol. 186, no. 22, pp. 4851-4867.e20. https://doi.org/10.1016/j.cell.2023.09.013

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title = "Serotonin reduction in post-acute sequelae of viral infection",

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.",

keywords = "Long COVID, neurocognitive symptoms, PASC, platelets, post-viral syndromes, serotonin, thrombocytopenia, type I interferons, vagus nerve, viral persistence",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1016/j.cell.2023.09.013",

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AU - Wong, Andrea C.

AU - Devason, Ashwarya S.

AU - Umana, Iboro C.

AU - Cox, Timothy O.

AU - Dohnalová, Lenka

AU - Litichevskiy, Lev

AU - Perla, Jonathan

AU - Lundgren, Patrick

AU - Etwebi, Zienab

AU - Izzo, Luke T.

AU - Kim, Jihee

AU - Tetlak, Monika

AU - Descamps, Hélène C.

AU - Park, Simone L.

AU - Wisser, Stephen

AU - McKnight, Aaron D.

AU - Pardy, Ryan D.

AU - Kim, Junwon

AU - Blank, Niklas

AU - Patel, Shaan

AU - Thum, Katharina

AU - Mason, Sydney

AU - Beltra, Jean Christophe

AU - Michieletto, Michaël F.

AU - Ngiow, Shin Foong

AU - Miller, Brittany M.

AU - Liou, Megan J.

AU - Madhu, Bhoomi

AU - Dmitrieva-Posocco, Oxana

AU - Huber, Alex S.

AU - Hewins, Peter

AU - Petucci, Christopher

AU - Chu, Candice P.

AU - Baraniecki-Zwil, Gwen

AU - Giron, Leila B.

AU - Baxter, Amy E.

AU - Greenplate, Allison R.

AU - Kearns, Charlotte

AU - Montone, Kathleen

AU - Litzky, Leslie A.

AU - Feldman, Michael

AU - Henao-Mejia, Jorge

AU - Striepen, Boris

AU - Ramage, Holly

AU - Jurado, Kellie A.

AU - Wellen, Kathryn E.

AU - O'Doherty, Una

AU - Abdel-Mohsen, Mohamed

AU - Landay, Alan L.

AU - Keshavarzian, Ali

AU - Henrich, Timothy J.

AU - Deeks, Steven G.

AU - Peluso, Michael J.

AU - Meyer, Nuala J.

AU - Wherry, E. John

AU - Abramoff, Benjamin A.

AU - Cherry, Sara

AU - Thaiss, Christoph A.

AU - Levy, Maayan

PY - 2023/10/26

Y1 - 2023/10/26

N2 - 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.

AB - 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.

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KW - neurocognitive symptoms

KW - PASC

KW - platelets

KW - post-viral syndromes

KW - serotonin

KW - thrombocytopenia

KW - type I interferons

KW - vagus nerve

KW - viral persistence

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SN - 0092-8674

VL - 186

SP - 4851-4867.e20

JO - Cell

JF - Cell

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ER -

Serotonin reduction in post-acute sequelae of viral infection

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Keywords

ASJC Scopus subject areas

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