EBioMedicine (Aug 2023)
Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infectionResearch in context
- Lihui Guo,
- Brent Appelman,
- Kirsten Mooij-Kalverda,
- Riekelt H. Houtkooper,
- Michel van Weeghel,
- Frédéric M. Vaz,
- Annemiek Dijkhuis,
- Tamara Dekker,
- Barbara S. Smids,
- Jan Willem Duitman,
- Marianna Bugiani,
- Paul Brinkman,
- Jonne J. Sikkens,
- H.A. Ayesha Lavell,
- Rob C.I. Wüst,
- Michèle van Vugt,
- René Lutter,
- M.A. van Agtmael,
- A.G. Algera,
- B. Appelman,
- F.E.H.P. van Baarle,
- M. Beudel,
- H.J. Bogaard,
- M. Bomers,
- P.I. Bonta,
- L.D.J. Bos,
- M. Botta,
- J. de Brabander,
- G.J. de Bree,
- S. de Bruin,
- M. Bugiani,
- E.B. Bulle,
- O. Chouchane,
- A.P.M. Cloherty,
- D. Buis,
- M.C.F.J. de Rotte,
- M. Dijkstra,
- D.A. Dongelmans,
- R.W.G. Dujardin,
- P.E. Elbers,
- L.M. Fleuren,
- S.E. Geerlings,
- T.B.H. Geijtenbeek,
- A.R.J. Girbes,
- A. Goorhuis,
- M.P. Grobusch,
- L.A. Hagens,
- J. Hamann,
- V.C. Harris,
- R. Hemke,
- S.M. Hermans,
- L.M.A. Heunks,
- M.W. Hollmann,
- J. Horn,
- J.W. Hovius,
- M.D. de Jong,
- R. Koing,
- E.H.T. Lim,
- N. van Mourik,
- J.F. Nellen,
- E.J. Nossent,
- F. Paulus,
- E. Peters,
- D. Piña-Fuentes,
- T. van der Poll,
- B. Preckel,
- J.M. Prins,
- S.J. Raasveld,
- T.D.Y. Reijnders,
- M. Schinkel,
- F.A.P. Schrauwen,
- M.J. Schultz,
- A.R. Schuurman,
- J. Schuurmans,
- K. Sigaloff,
- M.A. Slim,
- P. Smeele,
- M.R. Smit,
- C. Stijnis,
- W. Stilma,
- C.E. Teunissen,
- P. Thoral,
- A.M. Tsonas,
- P.R. Tuinman,
- M. van der Valk,
- D.P. Veelo,
- C. Volleman,
- H. de Vries,
- L.A. van Vught,
- M. van Vugt,
- D. Wouters,
- A.H. Zwinderman,
- M.C. Brouwer,
- W.J. Wiersinga,
- A.P.J. Vlaar,
- D. van de Beek
Affiliations
- Lihui Guo
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Brent Appelman
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Amsterdam Institute for Infection and Immunity, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Kirsten Mooij-Kalverda
- Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Riekelt H. Houtkooper
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam, the Netherlands
- Michel van Weeghel
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Frédéric M. Vaz
- Core Facility Metabolomics, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, the Netherlands
- Annemiek Dijkhuis
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Tamara Dekker
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Barbara S. Smids
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Jan Willem Duitman
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Marianna Bugiani
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Paul Brinkman
- Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Jonne J. Sikkens
- Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- H.A. Ayesha Lavell
- Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Rob C.I. Wüst
- Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
- Michèle van Vugt
- Division of Infectious Diseases, Department of Internal Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- René Lutter
- Department Experimental Immunology, Amsterdam Infection and Immunity Center, Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Corresponding author. Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
- M.A. van Agtmael
- A.G. Algera
- B. Appelman
- F.E.H.P. van Baarle
- M. Beudel
- H.J. Bogaard
- M. Bomers
- P.I. Bonta
- L.D.J. Bos
- M. Botta
- J. de Brabander
- G.J. de Bree
- S. de Bruin
- M. Bugiani
- E.B. Bulle
- O. Chouchane
- A.P.M. Cloherty
- D. Buis
- M.C.F.J. de Rotte
- M. Dijkstra
- D.A. Dongelmans
- R.W.G. Dujardin
- P.E. Elbers
- L.M. Fleuren
- S.E. Geerlings
- T.B.H. Geijtenbeek
- A.R.J. Girbes
- A. Goorhuis
- M.P. Grobusch
- L.A. Hagens
- J. Hamann
- V.C. Harris
- R. Hemke
- S.M. Hermans
- L.M.A. Heunks
- M.W. Hollmann
- J. Horn
- J.W. Hovius
- M.D. de Jong
- R. Koing
- E.H.T. Lim
- N. van Mourik
- J.F. Nellen
- E.J. Nossent
- F. Paulus
- E. Peters
- D. Piña-Fuentes
- T. van der Poll
- B. Preckel
- J.M. Prins
- S.J. Raasveld
- T.D.Y. Reijnders
- M. Schinkel
- F.A.P. Schrauwen
- M.J. Schultz
- A.R. Schuurman
- J. Schuurmans
- K. Sigaloff
- M.A. Slim
- P. Smeele
- M.R. Smit
- C. Stijnis
- W. Stilma
- C.E. Teunissen
- P. Thoral
- A.M. Tsonas
- P.R. Tuinman
- M. van der Valk
- D.P. Veelo
- C. Volleman
- H. de Vries
- L.A. van Vught
- M. van Vugt
- D. Wouters
- A.H. Zwinderman
- M.C. Brouwer
- W.J. Wiersinga
- A.P.J. Vlaar
- D. van de Beek
- Journal volume & issue
-
Vol. 94
p. 104729
Abstract
Summary: Background: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. Methods: Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. Findings: IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. Interpretation: SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. Funding: None.
