Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.

新型严重急性呼吸综合征冠状病毒2（novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）已蔓延至几乎所有大陆，全球累计死亡病例超125万例。目前人们对该病毒在宿主靶点上的致病效应的认知仍十分有限，这阻碍了我们对新型冠状病毒肺炎（Coronavirus Disease 2019, COVID-19）发病机制的理解以及治疗策略的开发。本研究采用全面的非靶向代谢组学（untargeted metabolomic）与脂质组学（untargeted lipidomic）分析方法，以捕捉宿主感染SARS-CoV-2后的应答反应。我们发现多种循环脂质可作为潜在生物标志物，例如磷脂酰胆碱（phosphatidylcholine）14:0_22:6（曲线下面积（area under the curve, AUC）=0.96）、磷脂酰胆碱16:1_22:6（AUC=0.97）以及磷脂酰乙醇胺（phosphatidylethanolamine）18:1_20:4（AUC=0.94）。此外，甘油三酯（triglycerides）与游离脂肪酸（free fatty acids），尤其是花生四烯酸（arachidonic acid, AUC=0.99）和油酸（oleic acid, AUC=0.98），与疾病严重程度密切相关。对非重症COVID-19患者的非靶向分析显示，患者体内脂质发生显著改变，同时苯丙氨酸（phenylalanine）、酪氨酸（tyrosine）与色氨酸（tryptophan）生物合成、苯丙氨酸代谢、氨酰-tRNA降解（aminoacyl-tRNA degradation）、花生四烯酸代谢以及三羧酸循环（tricarboxylic acid cycle, TCA循环）均出现紊乱。疾病严重程度的特征为糖异生（gluconeogenesis）与卟啉类物质（porphyrins）代谢被激活，这在感染进程中发挥关键作用。此外，本研究进一步证实，磷脂酶A2（phospholipase A2, PLA2）活性可作为COVID-19发病机制中的潜在关键因素以及潜在治疗靶点。截至目前，本研究是针对COVID-19患者与对照组血浆开展的规模最大的非靶向代谢组学与脂质组学分析，本研究明确了与宿主对COVID-19的应答相关的新机制、潜在血浆生物标志物以及治疗靶点。