AhR and IDO1 in pathogenesis of Covid-19 and the “Systemic AhR Activation Syndrome:” a translational review and therapeutic perspectives

Abstract

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a “Systemic AhR Activation Syndrome” (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Taste and Smell Disorders in COVID-19 Patients: Role of Interleukin-6

“… 35 Turski et al have supposed that the loss of smell is due to the infection of the support cells and vascular pericytes of the olfactory epithelium and bulb with consequent alteration of the function of the olfactory neurons. 35 …”

Clinical Impact Potential of Supplemental Nutrients as Adjuncts of Therapy in High-Risk COVID-19 for Obese Patients

“…After ACE2 mediated cell entry, coronaviruses firstly activate aryl hydrocarbon receptors (AhRs) without indoleamine 2,3dioxygenase (IDO1) stimulation (141). Activated AhRs initiates the production of inflammation factors (IL-1β, IL-6, and TNF-α), induces tissue factor (TF) and PAI-1 mediated thromboembolism (AhR-TF/PAI-1 pathway) (142), and lead multiple organ fibrosis via Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1)/IL-22 signaling pathway with signal transducer and activator of transcription 3 (STAT3) (143).…”

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

“…Activation of the kynunenine pathway in IDO-competent cells, such as antigen-presenting cells and epithelial cells, restrains inflammation and induces long-term immune tolerance via the following mechanisms: (i) Trp depletion activates the general control non-depressible 2 (GCN2) stress kinase in dendritic cells and macrophages enhancing the production of anti-inflammatory cytokines and causing differentiation and recruitment of T reg cells [ 6 ]; (ii) Kyn binds to, and activates, the aryl hydrocarbon receptor (AhR) in both dendritic cells (DCs) and T cells. This promotes the conversion of T effector cells into T reg cells, and also promotes IDO induction, thereby creating a Kyn/AhR/IDO loop that sustains immune suppression [ 7 , 8 ]; interestingly, AhR has been implicated in the pathogenesis of SARS-CoV2 infection [ 9 , 10 ]; (iii) other kynurenine metabolites, e.g. , kynurenic, 3-hydroxyanthranilic, and cinnabarinic acids, display antinflammatory action and promote immune tolerance [ 11 ]; and (iv) IDO-1 may lead to immune tolerance independently of its enzymatic activity by acting as a signaling molecule in dendritic cells [ 12 , 13 ].…”