Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection
Lihui Guo, Brent Appelman, Kirsten Mooij‐Kalverda, Riekelt H. Houtkooper, Michel van Weeghel, Frédéric M. Vaz, Annemiek Dijkhuis, Tamara Dekker, Barbara Smids, JanWillem 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, Anna Geke Algera, Brent Appelman, Frank E.H.P. van Baarle, Martijn Beudel, Harm Jan Bogaard, Marije K. Bomers, Peter I. Bonta, Lieuwe D. J. Bos, Michela Botta, Justin de Brabander, Godelieve J. de Bree, Sanne de Bruin, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Dennis R. Buis, Maurits C. F. J. de Rotte, Maartje Dijkstra, Dave A. Dongelmans, Romein W. G. Dujardin, Paul Elbers, Lucas M. Fleuren, Suzanne E. Geerlings, Teunis B. H. Geijtenbeek, Armand R. J. Girbes, Abraham Goorhuis, Martin P. Grobusch, Laura A. Hagens, Jörg Hamann, Vanessa Harris, Robert Hemke, Sabine Hermans, Leo Heunks, Markus W. Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, R. Koing, Endry H. T. Lim, Niels van Mourik, J.F. Nellen, Esther J. Nossent, Frederique Paulus, Edgar J.G. Peters, Dan Piña‐Fuentes, Tom van der Poll, Benedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom D. Y. Reijnders, Michiel Schinkel, Femke A. P. Schrauwen, Marcus J. Schultz, Alex R. Schuurman, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry R. Smit, Cornelis Stijnis, Willemke Stilma, Charlotte E. Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. van Vught, Michèle van Vugt, Dorien Wouters, Aeilko H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P. J. Vlaar, Diederik van de Beek
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.