Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Cell. 2023 Oct 26;186(22):4851-4867.e20. doi: 10.1016/j.cell.2023.09.013. Epub 2023 Oct 16.
Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
新型冠状病毒肺炎（COVID-19）的急性后期后遗症（PASC，“长新冠”）对全球健康构成重大挑战。其发病机制尚不清楚，迄今为止尚未发现有效的治疗方法。目前已经提出了几种假设来解释 PASC 的病因，包括病毒持续存在、慢性炎症、高凝状态和自主神经功能障碍。在这里，我们提出了一个将这四种假说联系在一个单一途径中的机制，并为治疗干预提供了可行的见解。我们发现 PASC 与血清素减少有关。病毒感染和 I 型干扰素驱动的炎症通过三种机制降低血清素：减少肠道对血清素前体色氨酸的吸收；血小板过度激活和血小板减少，影响血清素储存；以及增强 MAO 介导的血清素周转。反过来，外周血清素减少会阻碍迷走神经的活动，从而损害海马体的反应和记忆。这些发现为与长新冠中病毒持续存在相关的神经认知症状提供了一个可能的解释，这种症状可能会延伸到其他病毒性综合征。
