Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.
Apoptosis
Autophagy
IDO2
Kynurenine
Mitochondrial_activity
PASC
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Aug 2023
Aug 2023
Historique:
received:
08
11
2022
revised:
08
06
2023
accepted:
12
07
2023
medline:
14
8
2023
pubmed:
29
7
2023
entrez:
28
7
2023
Statut:
ppublish
Résumé
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. 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. 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. 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. None.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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
BACKGROUND
None.
Identifiants
pubmed: 37506544
pii: S2352-3964(23)00294-3
doi: 10.1016/j.ebiom.2023.104729
pmc: PMC10406961
pii:
doi:
Substances chimiques
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
IDO2 protein, human
0
Types de publication
Observational Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104729Investigateurs
M A van Agtmael
(MA)
A G Algera
(AG)
B Appelman
(B)
F E H P van Baarle
(FEHP)
M Beudel
(M)
H J Bogaard
(HJ)
M Bomers
(M)
P I Bonta
(PI)
L D J Bos
(LDJ)
M Botta
(M)
J de Brabander
(J)
G J de Bree
(GJ)
S de Bruin
(S)
M Bugiani
(M)
E B Bulle
(EB)
O Chouchane
(O)
A P M Cloherty
(APM)
D Buis
(D)
M C F J de Rotte
(MCFJ)
M Dijkstra
(M)
D A Dongelmans
(DA)
R W G Dujardin
(RWG)
P E Elbers
(PE)
L M Fleuren
(LM)
S E Geerlings
(SE)
T B H Geijtenbeek
(TBH)
A R J Girbes
(ARJ)
A Goorhuis
(A)
M P Grobusch
(MP)
L A Hagens
(LA)
J Hamann
(J)
V C Harris
(VC)
R Hemke
(R)
S M Hermans
(SM)
L M A Heunks
(LMA)
M W Hollmann
(MW)
J Horn
(J)
J W Hovius
(JW)
M D de Jong
(MD)
R Koing
(R)
E H T Lim
(EHT)
N van Mourik
(N)
J F Nellen
(JF)
E J Nossent
(EJ)
F Paulus
(F)
E Peters
(E)
D Piña-Fuentes
(D)
T van der Poll
(T)
B Preckel
(B)
J M Prins
(JM)
S J Raasveld
(SJ)
T D Y Reijnders
(TDY)
M Schinkel
(M)
F A P Schrauwen
(FAP)
M J Schultz
(MJ)
A R Schuurman
(AR)
J Schuurmans
(J)
K Sigaloff
(K)
M A Slim
(MA)
P Smeele
(P)
M R Smit
(MR)
C Stijnis
(C)
W Stilma
(W)
C E Teunissen
(CE)
P Thoral
(P)
A M Tsonas
(AM)
P R Tuinman
(PR)
M van der Valk
(M)
D P Veelo
(DP)
C Volleman
(C)
H de Vries
(H)
L A van Vught
(LA)
M van Vugt
(M)
D Wouters
(D)
A H Zwinderman
(AH)
M C Brouwer
(MC)
W J Wiersinga
(WJ)
A P J Vlaar
(APJ)
D van de Beek
(D)
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.