4.8 Article

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

Journal

THERANOSTICS
Volume 11, Issue 16, Pages 8008-8026

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/thno.61832

Keywords

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Funding

  1. National Science and Technology Major Project [2018ZX10101004]
  2. National Natural Science Foundation of China [81873964, 31930021, 31970633, 34671360, 31670161]
  3. CAS Youth Innovation Promotion Association [2020332]
  4. program for HUST Academic Frontier Youth Team

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The study identified specific alterations in plasma proteomic and metabolomic profiles of children with COVID-19, showing a distinct molecular response compared to adults. This suggests potential differences in pathogenesis and immune response mechanisms between children and adults.
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.

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