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.

中文翻译：

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AhR 和 IDO1 在 Covid-19 发病机制和“系统性 AhR 激活综合征：”转化综述和治疗观点中的作用。

摘要

Covid-19 是由 SARS-CoV-2 引起的急性疾病，最初的临床症状包括咳嗽、发烧、不适、头痛和嗅觉丧失等。进入细胞后，冠状病毒 (CoV) 通过吲哚胺 2,3-双加氧酶 (IDO1) 独立机制激活芳基烃受体 (AhR)，绕过 IDO1-犬尿氨酸-AhR 途径。IDO1-犬尿氨酸-AhR 信号通路被多种病毒、微生物和寄生病原体用来激活 AhR 并建立感染。AhR 通过 IDO1-AhR-IDO1 正反馈回路增强自身活性，延长病原体诱导的激活。冠状病毒对 AhR 的直接激活会诱导多种 AhR 依赖性下游效应器立即同时上调，这反过来又会导致由炎症、血栓栓塞和纤维化组成的“系统性 AhR 激活综合征”(SAAS)，最终导致多器官损伤，甚至死亡。冠状病毒对 AhR 的激活可能会导致不同的表型疾病情况，具体取决于感染后的时间、总体健康状况、激素平衡、年龄、性别、合并症，以及调节 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，应该会降低感染的严重程度。尽管目前缺乏选择性下调 AhR 和 IDO1 的疗法，但临床使用的药物（如地塞米松）可能会下调 AhR 和 IDO1 基因，因为骨化三醇/维生素 D ₃可能下调 AhR 基因，而生育酚/维生素 E 可能会下调 AhR 基因。可能下调 IDO1 基因。因此，补充骨化三醇应进行流行病学研究，并在预防 CoV 感染的前瞻性试验中进行测试，生育酚也应如此，而地塞米松则可在介入试验中尝试。由于缺乏体育锻炼会通过 IDO1-犬尿氨酸-AhR 信号通路激活 AhR，从而增加感染风险，因此在大流行爆发期间的隔离和居家令期间应鼓励体育锻炼。了解哪些因素影响 AhR 和 IDO1 的基因表达可能有助于设计预防和治疗人类感染 Covid-19 的疗法。