PMID- 37506544
OWN - NLM
STAT- MEDLINE
DCOM- 20230817
LR  - 20230817
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 94
DP  - 2023 Aug
TI  - Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress 
      in post-acute sequelae of SARS-CoV-2 infection.
PG  - 104729
LID - S2352-3964(23)00294-3 [pii]
LID - 10.1016/j.ebiom.2023.104729 [doi]
LID - 104729
AB  - 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.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Guo, Lihui
AU  - Guo L
AD  - 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.
FAU - Appelman, Brent
AU  - Appelman B
AD  - 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.
FAU - Mooij-Kalverda, Kirsten
AU  - Mooij-Kalverda K
AD  - Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of 
      Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
FAU - Houtkooper, Riekelt H
AU  - Houtkooper RH
AD  - 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.
FAU - van Weeghel, Michel
AU  - van Weeghel M
AD  - 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.
FAU - Vaz, Frederic M
AU  - Vaz FM
AD  - 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.
FAU - Dijkhuis, Annemiek
AU  - Dijkhuis A
AD  - 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.
FAU - Dekker, Tamara
AU  - Dekker T
AD  - 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.
FAU - Smids, Barbara S
AU  - Smids BS
AD  - 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.
FAU - Duitman, Jan Willem
AU  - Duitman JW
AD  - 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.
FAU - Bugiani, Marianna
AU  - Bugiani M
AD  - Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 
      the Netherlands.
FAU - Brinkman, Paul
AU  - Brinkman P
AD  - Department Pulmonary Medicine, Amsterdam UMC, location AMC, University of 
      Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
FAU - Sikkens, Jonne J
AU  - Sikkens JJ
AD  - Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 
      Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
FAU - Lavell, H A Ayesha
AU  - Lavell HAA
AD  - Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 
      Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
FAU - Wust, Rob C I
AU  - Wust RCI
AD  - Laboratory for Myology, Department of Human Movement Sciences, Faculty of 
      Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam 
      Movement Sciences, Amsterdam, the Netherlands.
FAU - van Vugt, Michele
AU  - van Vugt M
AD  - Division of Infectious Diseases, Department of Internal Medicine, Amsterdam UMC, 
      location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the 
      Netherlands.
FAU - Lutter, Rene
AU  - Lutter R
AD  - 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. 
      Electronic address: r.lutter@amsterdamumc.nl.
CN  - Amsterdam UMC COVID-19 Biobank study Group
LA  - eng
PT  - Journal Article
PT  - Observational Study
DEP - 20230726
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 343-65-7 (Kynurenine)
RN  - 8DUH1N11BX (Tryptophan)
RN  - 0 (IDO2 protein, human)
SB  - IM
MH  - Humans
MH  - Chromatography, Liquid
MH  - *COVID-19/complications
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
MH  - Kynurenine
MH  - Leukocytes, Mononuclear/metabolism
MH  - Post-Acute COVID-19 Syndrome
MH  - SARS-CoV-2/metabolism
MH  - Tandem Mass Spectrometry
MH  - *Tryptophan/metabolism
PMC - PMC10406961
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - IDO2
OT  - Kynurenine
OT  - Mitochondrial_activity
OT  - PASC
COIS- Declaration of interests The authors declare no competing interests.
FIR - van Agtmael, M A
IR  - van Agtmael MA
FIR - Algera, A G
IR  - Algera AG
FIR - Appelman, B
IR  - Appelman B
FIR - van Baarle, F E H P
IR  - van Baarle FEHP
FIR - Beudel, M
IR  - Beudel M
FIR - Bogaard, H J
IR  - Bogaard HJ
FIR - Bomers, M
IR  - Bomers M
FIR - Bonta, P I
IR  - Bonta PI
FIR - Bos, L D J
IR  - Bos LDJ
FIR - Botta, M
IR  - Botta M
FIR - de Brabander, J
IR  - de Brabander J
FIR - de Bree, G J
IR  - de Bree GJ
FIR - de Bruin, S
IR  - de Bruin S
FIR - Bugiani, M
IR  - Bugiani M
FIR - Bulle, E B
IR  - Bulle EB
FIR - Chouchane, O
IR  - Chouchane O
FIR - Cloherty, A P M
IR  - Cloherty APM
FIR - Buis, D
IR  - Buis D
FIR - de Rotte, M C F J
IR  - de Rotte MCFJ
FIR - Dijkstra, M
IR  - Dijkstra M
FIR - Dongelmans, D A
IR  - Dongelmans DA
FIR - Dujardin, R W G
IR  - Dujardin RWG
FIR - Elbers, P E
IR  - Elbers PE
FIR - Fleuren, L M
IR  - Fleuren LM
FIR - Geerlings, S E
IR  - Geerlings SE
FIR - Geijtenbeek, T B H
IR  - Geijtenbeek TBH
FIR - Girbes, A R J
IR  - Girbes ARJ
FIR - Goorhuis, A
IR  - Goorhuis A
FIR - Grobusch, M P
IR  - Grobusch MP
FIR - Hagens, L A
IR  - Hagens LA
FIR - Hamann, J
IR  - Hamann J
FIR - Harris, V C
IR  - Harris VC
FIR - Hemke, R
IR  - Hemke R
FIR - Hermans, S M
IR  - Hermans SM
FIR - Heunks, L M A
IR  - Heunks LMA
FIR - Hollmann, M W
IR  - Hollmann MW
FIR - Horn, J
IR  - Horn J
FIR - Hovius, J W
IR  - Hovius JW
FIR - de Jong, M D
IR  - de Jong MD
FIR - Koing, R
IR  - Koing R
FIR - Lim, E H T
IR  - Lim EHT
FIR - van Mourik, N
IR  - van Mourik N
FIR - Nellen, J F
IR  - Nellen JF
FIR - Nossent, E J
IR  - Nossent EJ
FIR - Paulus, F
IR  - Paulus F
FIR - Peters, E
IR  - Peters E
FIR - Pina-Fuentes, D
IR  - Pina-Fuentes D
FIR - van der Poll, T
IR  - van der Poll T
FIR - Preckel, B
IR  - Preckel B
FIR - Prins, J M
IR  - Prins JM
FIR - Raasveld, S J
IR  - Raasveld SJ
FIR - Reijnders, T D Y
IR  - Reijnders TDY
FIR - Schinkel, M
IR  - Schinkel M
FIR - Schrauwen, F A P
IR  - Schrauwen FAP
FIR - Schultz, M J
IR  - Schultz MJ
FIR - Schuurman, A R
IR  - Schuurman AR
FIR - Schuurmans, J
IR  - Schuurmans J
FIR - Sigaloff, K
IR  - Sigaloff K
FIR - Slim, M A
IR  - Slim MA
FIR - Smeele, P
IR  - Smeele P
FIR - Smit, M R
IR  - Smit MR
FIR - Stijnis, C
IR  - Stijnis C
FIR - Stilma, W
IR  - Stilma W
FIR - Teunissen, C E
IR  - Teunissen CE
FIR - Thoral, P
IR  - Thoral P
FIR - Tsonas, A M
IR  - Tsonas AM
FIR - Tuinman, P R
IR  - Tuinman PR
FIR - van der Valk, M
IR  - van der Valk M
FIR - Veelo, D P
IR  - Veelo DP
FIR - Volleman, C
IR  - Volleman C
FIR - de Vries, H
IR  - de Vries H
FIR - van Vught, L A
IR  - van Vught LA
FIR - van Vugt, M
IR  - van Vugt M
FIR - Wouters, D
IR  - Wouters D
FIR - Zwinderman, A H
IR  - Zwinderman AH
FIR - Brouwer, M C
IR  - Brouwer MC
FIR - Wiersinga, W J
IR  - Wiersinga WJ
FIR - Vlaar, A P J
IR  - Vlaar APJ
FIR - van de Beek, D
IR  - van de Beek D
EDAT- 2023/07/29 06:41
MHDA- 2023/08/14 06:43
PMCR- 2023/07/26
CRDT- 2023/07/28 18:05
PHST- 2022/11/08 00:00 [received]
PHST- 2023/06/08 00:00 [revised]
PHST- 2023/07/12 00:00 [accepted]
PHST- 2023/08/14 06:43 [medline]
PHST- 2023/07/29 06:41 [pubmed]
PHST- 2023/07/28 18:05 [entrez]
PHST- 2023/07/26 00:00 [pmc-release]
AID - S2352-3964(23)00294-3 [pii]
AID - 104729 [pii]
AID - 10.1016/j.ebiom.2023.104729 [doi]
PST - ppublish
SO  - EBioMedicine. 2023 Aug;94:104729. doi: 10.1016/j.ebiom.2023.104729. Epub 2023 Jul 
      26.