Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China.
Department of Infectious Diseases, Guangzhou Women and Childrens Medical Center, Guangzhou, 510120, China.
Theranostics. 2021 Jul 6;11(16):8008-8026. doi: 10.7150/thno.61832. eCollection 2021.
Children usually develop less severe symptoms responding to Coronavirus Disease 2019 (COVID-19) than adults. However, little is known about the molecular alterations and pathogenesis of COVID-19 in children. We conducted plasma proteomic and metabolomic profilings of the blood samples of a cohort containing 18 COVID-19-children with mild symptoms and 12 healthy children, which were enrolled from hospital admissions and outpatients, respectively. Statistical analyses were performed to identify molecules specifically altered in COVID-19-children. We also developed a machine learning-based pipeline named inference of biomolecular combinations with minimal bias (iBM) to prioritize proteins and metabolites strongly altered in COVID-19-children, and experimentally validated the predictions. By comparing to the multi-omic data in adults, we identified 44 proteins and 249 metabolites differentially altered in COVID-19-children against healthy children or COVID-19-adults. Further analyses demonstrated that both deteriorative immune response/inflammation processes and protective antioxidant or anti-inflammatory processes were markedly induced in COVID-19-children. Using iBM, we prioritized two combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish COVID-19-children from healthy children or COVID-19-adults. Further experiments validated that all the 5 proteins were up-regulated upon coronavirus infection. Interestingly, we found that the prioritized metabolites inhibited the expression of pro-inflammatory factors, and two of them, methylmalonic acid (MMA) and mannitol, also suppressed coronaviral replication, implying a protective role of these metabolites in COVID-19-children. The finding of a strong antagonism of deteriorative and protective effects provided new insights on the mechanism and pathogenesis of COVID-19 in children that mostly underwent mild symptoms. The identified metabolites strongly altered in COVID-19-children could serve as potential therapeutic agents of COVID-19.
儿童感染 2019 冠状病毒病（COVID-19）的症状通常比成人轻。然而，儿童感染 COVID-19 的分子改变和发病机制知之甚少。我们对包含 18 名轻症 COVID-19 患儿和 12 名健康儿童的队列的血液样本进行了血浆蛋白质组学和代谢组学分析，这些患儿分别来自住院和门诊。我们进行了统计分析以确定 COVID-19 患儿中特异性改变的分子。我们还开发了一种名为最小偏倚生物分子组合推断（iBM）的基于机器学习的管道，用于确定 COVID-19 患儿中强烈改变的蛋白质和代谢物，并对预测结果进行了实验验证。通过与成人的多组学数据进行比较，我们在 COVID-19 患儿中发现了 44 种蛋白质和 249 种代谢物与健康儿童或 COVID-19 成人相比发生了差异改变。进一步的分析表明，COVID-19 患儿中既存在恶化的免疫反应/炎症过程，也存在保护性抗氧化或抗炎过程。使用 iBM，我们确定了两个组合，每个组合分别包含 5 种蛋白质和 5 种代谢物，每个组合的总曲线下面积（AUC）值均为 100%，可准确区分 COVID-19 患儿与健康儿童或 COVID-19 成人。进一步的实验验证了所有 5 种蛋白质在冠状病毒感染后均上调。有趣的是，我们发现，所确定的代谢物抑制了促炎因子的表达，其中两种代谢物，即甲基丙二酸（MMA）和甘露醇，也抑制了冠状病毒的复制，这表明这些代谢物在 COVID-19 患儿中具有保护作用。这些发现为儿童 COVID-19 的发病机制提供了新的见解，即主要表现为轻症的 COVID-19 患儿中存在恶化和保护作用的强烈拮抗。在 COVID-19 患儿中强烈改变的代谢物可以作为 COVID-19 的潜在治疗药物。
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