Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
Department of Biopharmacy, Faculty of Pharmacy, Medical University, Lublin, Poland.
Restor Neurol Neurosci. 2020;38(4):343-354. doi: 10.3233/RNN-201042.
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.
新型冠状病毒肺炎（COVID-19）是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的急性疾病，最初的临床症状包括咳嗽、发热、乏力、头痛和嗅觉丧失。冠状病毒（CoV）通过吲哚胺 2,3-双加氧酶（IDO1）非依赖性机制激活芳香烃受体（AhR），绕过 IDO1-犬尿氨酸-AhR 途径。许多病毒、微生物和寄生虫病原体利用 IDO1-犬尿氨酸-AhR 信号通路来激活 AhR，从而建立感染。AhR 通过 IDO1-AhR-IDO1 正反馈环增强自身活性，从而延长病原体诱导的激活时间。CoV 对 AhR 的直接激活导致多种 AhR 依赖性下游效应物的即时和同时上调，进而导致“全身性 AhR 激活综合征”（SAAS），包括炎症、血栓栓塞和纤维化，最终导致多器官损伤和死亡。CoV 对 AhR 的激活可能导致不同的疾病表型，具体取决于感染后时间、整体健康状况、激素平衡、年龄、性别、合并症，但也取决于调节 AhR 的饮食和环境因素。我们假设消除已知上调 AhR 的因素，或实施已知下调 AhR 的措施，应降低感染的严重程度。虽然目前缺乏选择性下调 AhR 和 IDO1 的治疗方法，但临床使用的药物，如地塞米松，可能下调 AhR 和 IDO1 基因，而钙三醇/维生素 D3 可能下调 AhR 基因，生育酚/维生素 E 可能下调 IDO1 基因。因此，应该对钙三醇进行流行病学研究，并在预防 COVID-19 感染的前瞻性试验中进行测试，也应该对生育酚进行测试，而地塞米松可以在干预试验中进行测试。由于缺乏体育锻炼会通过 IDO1-犬尿氨酸-AhR 信号通路激活 AhR，增加感染风险，因此在大流行爆发期间的隔离和居家令期间应鼓励进行体育锻炼。了解哪些因素会影响 AhR 和 IDO1 的基因表达，可能有助于设计预防和治疗 COVID-19 患者的治疗方法。
