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.
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.
EBioMedicine. 2023 Aug;94:104729. doi: 10.1016/j.ebiom.2023.104729. Epub 2023 Jul 26.
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.
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SARS-CoV-2 感染的后期后遗症（PASC）包括疲劳、劳累后不适和认知问题。在致命/严重 COVID-19 中丰富表达色氨酸分解酶吲哚胺 2,3-双加氧酶-2（IDO2），促使我们在一项探索性观察研究中确定 IDO2 是否在 PASC 中表达和活跃，并可能与病理生理学相关。
从特征明确的 PASC 患者和无 PASC 的 SARS-CoV-2 感染个体中获得血浆或血清和外周血单核细胞（PBMC）。我们通过 UPLC-MS/MS 评估色氨酸及其降解产物。通过免疫组织化学（IHC）检测 IDO2、IDO1、AHR、犬尿氨酸代谢物、自噬和凋亡，在另一批 PASC 队列的 PBMC 中确定 IDO2 活性、其潜在后果以及 AHR 在 IDO2 表达中的作用。这些 PBMC 还通过代谢组学和呼吸仪进行线粒体功能分析。还对来自两名 PASC 患者的尸检脑组织进行了 IHC 检测。
IDO2 在 PASC 患者的 PBMC 中表达和活跃，并且在 SARS-CoV-2 感染后很长时间内都存在。这与自噬平行，在血液细胞中表现为线粒体功能降低、细胞内氨基酸和三羧酸循环相关化合物水平降低。IDO2 表达和活性是由 SARS-CoV-2 感染引发的，但 SARS-CoV-2 诱导的病理严重程度似乎与产生的特定犬尿氨酸代谢物有关。在体外，IDO2 表达和自噬可以被 AHR 拮抗剂阻断。
SARS-CoV-2 感染引发持久的 IDO2 表达，可被 AHR 拮抗剂阻断。特定的犬尿氨酸代谢物可能与 SARS-CoV-2 诱导的症状和病理有关。
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