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Multi-omic profiling of plasma reveals molecular alterations in children with COVID-19
Chong Wang1,2,3, Xufang Li1,2, Wanshan Ning4
1Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China.
Insights
Children with Coronavirus Disease 2019 (COVID-19) show distinct molecular changes, including protective metabolites like methylmalonic acid (MMA) and mannitol that may inhibit viral replication and inflammation.
Area of Science:
- Pediatric infectious diseases
- Molecular biology
- Immunology
Background:
- Children typically experience milder Coronavirus Disease 2019 (COVID-19) than adults.
- Limited understanding exists regarding the molecular pathogenesis of COVID-19 in pediatric populations.
Purpose of the Study:
- To investigate molecular alterations in children with mild COVID-19.
- To identify potential biomarkers and therapeutic targets for pediatric COVID-19.
Main Methods:
- Plasma proteomic and metabolomic profiling of 18 COVID-19-children and 12 healthy children.
- Utilized a machine learning pipeline (inference of biomolecular combinations with minimal bias - iBM) for data analysis.
- Experimental validation of prioritized molecular targets.
Main Results:
- Identified 44 proteins and 249 metabolites differentially altered in COVID-19-children compared to controls.
- Observed induction of both inflammatory and protective (antioxidant/anti-inflammatory) processes.
- Prioritized 5 proteins and 5 metabolites with high diagnostic accuracy (AUC 100%).
- Validated protein upregulation and identified specific metabolites (methylmalonic acid, mannitol) inhibiting inflammation and viral replication.
Conclusions:
- A balance between detrimental and protective molecular effects is observed in pediatric COVID-19.
- Specific metabolites show potential as therapeutic agents for COVID-19 in children.
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.
