Multi-omic profiling of plasma reveals molecular alterations in children with COVID-19

Abstract

Rationale: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. Methods: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. Results: 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. Conclusion: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.

Plasma proteomic and metabolomic characterization of COVID-19 survivors 6 months after discharge

“…The de-clustering potential (DP) and collision energy (CE) for individual MRM transitions were obtained with further DP and CE optimization. The quantification of metabolites was accomplished using the targeted MRM approach [ 69 ]. A specific set of MRM transitions were monitored for each period according to the metabolites within this period.…”

COVIDomics: The Proteomic and Metabolomic Signatures of COVID-19

“…In addition, the multiomic profiling of the plasma of the 18 COVID-19 children with mild symptoms of Wang et al [ 79 ] detected 44 differential proteins and 249 metabolites, which enriched platelet degranulation, plasminogen activation, fibrinolysis, blood coagulation, extracellular matrix organization as biological processes, and altered biosynthesis of amino acids (arginine metabolism), or other KEGGs such as carbon metabolism, choline metabolism, pyrimidine metabolism, etc. Machine-learning-based inference analysis revealed two combinations of five proteins (ENO1, F9, F11, FGA, FGG) and five metabolites (dihydroorotic acid, indoleacetaldehyde, mannitol, methylmalonic acid, tryptophan) able to accurately discriminate COVID-19 children.…”

“… The main findings obtained from the review of proteomics studies are summarized. In particular, the results from plasma [ 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ] and serum [ 43 , 44 , 45 , 46 , 47 , 83 , 86 ] studies were merged to identify the common proteins (top) that should represent the proteome signature of COVID-19. These protein entries were analyzed and clustered using STRING version 11.5, revealing the formation of three main clusters (bottom).…”

Small-molecule metabolome identifies potential therapeutic targets against COVID-19

“…We observed a decrease in levels of MetSO, a product of oxidative stress 41 in patients with COVID-19 compared to those with Influenza and RSV. While previous studies have documented an increase in MetSO in the serum and plasma of COVID-19 patients compared to healthy controls 8 , 42 – 44 there have been no studies prior to ours comparing such levels between COVID-19, Influenza and RSV respectively in the respiratory tract. In influenza an increase in pro-oxidative markers such as NAPDH oxidase occurs in infection and can cause severe lung injury 45 while in RSV expression of antioxidant markers including catalase is decreased 46 .…”