@article{b3effa3e3a454182b292b9cf4f62a013,
title = "Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection",
abstract = "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.",
keywords = "Apoptosis, Autophagy, IDO2, Kynurenine, Mitochondrial_activity, PASC",
author = "{Amsterdam UMC COVID-19 biobank study group} and Lihui Guo and Brent Appelman and Kirsten Mooij-Kalverda and Houtkooper, {Riekelt H.} and {van Weeghel}, Michel and Vaz, {Fr{\'e}d{\'e}ric M.} and Annemiek Dijkhuis and Tamara Dekker and Smids, {Barbara S.} and Duitman, {Jan Willem} and Marianna Bugiani and Paul Brinkman and Sikkens, {Jonne J.} and Lavell, {H. A.Ayesha} and W{\"u}st, {Rob C.I.} and {van Vugt}, Mich{\`e}le and Ren{\'e} Lutter and {van Agtmael}, {M. A.} and Algera, {A. G.} and {van Baarle}, {F. E.H.P.} and M. Beudel and Bogaard, {H. J.} and M. Bomers and Bonta, {P. I.} and Bos, {L. D.J.} and M. Botta and {de Brabander}, J. and {de Bree}, {G. J.} and {de Bruin}, S. and M. Bugiani and Bulle, {E. B.} and O. Chouchane and Cloherty, {A. P.M.} and D. Buis and {de Rotte}, {M. C.F.J.} and M. Dijkstra and Dongelmans, {D. A.} and Fleuren, {L. M.} and Geerlings, {S. E.} and R. Hemke and Hermans, {S. M.} and Nossent, {E. J.} and E. Peters and Prins, {J. M.} and Schuurman, {A. R.} and K. Sigaloff and Teunissen, {C. E.} and P. Thoral and Tuinman, {P. R.} and {de Vries}, H. and Geijtenbeek, {T. B. H.} and A. Goorhuis and Grobusch, {M. P.} and Hagens, {L. A.} and J. Hamann and Harris, {V. C.} and Hollmann, {M. W.} and J. Horn and Hovius, {J. W.} and {de Jong}, {M. D.} and Lim, {E. H. T.} and {van Mourik}, N. and Nellen, {J. F.} and F. Paulus and {van der Poll}, T. and B. Preckel and Raasveld, {S. J.} and Reijnders, {T. D. Y.} and M. Schinkel and Schrauwen, {F. A. P.} and Schultz, {M. J.} and J. Schuurmans and Slim, {M. A.} and P. Smeele and Smit, {M. R.} and C. Stijnis and W. Stilma and Tsonas, {A. M.} and {van der Valk}, M. and Veelo, {D. P.} and C. Volleman and {van Vught}, {L. A.} and Zwinderman, {A. H.} and Brouwer, {M. C.} and Wiersinga, {W. J.} and Vlaar, {A. P. J.} and {van de Beek}, D.",
note = "Funding Information: We thank all patients and healthy volunteers for their participation. This study was funded by the involved researchers. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = aug,
day = "1",
doi = "https://doi.org/10.1016/j.ebiom.2023.104729",
language = "English",
volume = "94",
pages = "104729",
journal = "eBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}