Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children

Background: Children usually develop less severe disease responding to COVID-19 than adults. However, little is known about the detailed mechanism and pathogenesis of children with COVID-19 (CC), and its difference to adults with COVID-19 (AC).Methods: We conducted a plasma proteomic and metabolomic profiling, using the blood samples of 30 children including 18 CC cases and 12 healthy children (HC). By comparing the multi-omic data of AC, standard statistical tests were used to identify differentially expressed proteins (DEPs) and metabolites (DEMs) exclusively altered in CC. Enrichment analyses were conducted to identify biological processes/pathways specifically enriched in CC. To identify potential CC-specific biomarkers, we developed a new machine learning-based method named inference of biomarker combinations with minimal bias (iBM). Further experiments were conducted to validate the predicted metabolic markers.Findings: By quantifying 757 proteins and 1174 metabolites, we identified 44 DEPs and 249 DEMs exclusively altered in CC. Enrichment analyses demonstrated that in CC both deleterious immune response/inflammation processes and protective anti-inflammatory processes were strongly induced in the proteomic level, whereas protective anabolism-related processes were enriched in the metabolomic level. Using iBM, we prioritized two CC-specific biomarker combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish CC from HC or AC. Further experiments showed that the identified metabolites not only inhibited the expression of pro-inflammatory factors, but also suppressed coronaviral replication, implying that these factors played key roles in protecting pediatric patients from both viral infection and infection-induced inflammation.Interpretation: The finding of a strong antagonism of deleterious and protective effects provided new insights on the mechanism and pathogenesis of CC cases that mostly undergo mild symptoms. The identified CC-specific biomarkers could serve as candidate drug targets or therapeutic agents of COVID-19.Funding Statement: This work was supported by the Strategic Priority Research Program of CAS (XDB29010300 to X.Z.), the National Science and Technology Major Project (2018ZX10101004 to X.Z.), National Natural Science Foundation of China (81873964 to Y.Q., 31930021, 31970633 and 34671360 to Y.X., and 31670161 to X.Z.), Grant from the CAS Youth Innovation Promotion Association (2020332 to Y.Q.), the program for HUST Academic Frontier Youth Team (Y.X.).Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: All work performed in this study was approved by the Guangzhou Women and Children's Medical Center Ethics Committee and Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious diseases.