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A Multi-omics Longitudinal Study Reveals Alteration of the Leukocyte Activation Pathway in COVID-19 Patients
Kruthi Suvarna1, Akanksha Salkar1, Viswanthram Palanivel1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Insights
Severe coronavirus disease 2019 (COVID-19) infection involves dysregulated immune responses. This study identifies key protein and metabolite signatures, highlighting leukocyte activation and arginine metabolism as potential therapeutic targets for COVID-19.
Area of Science:
- Biochemistry
- Immunology
- Proteomics
Background:
- Severe coronavirus disease 2019 (COVID-19) can cause critical illness, with cytokine storm linked to fatalities.
- The precise molecular mechanisms underlying the heightened immune response in severe COVID-19 remain incompletely understood.
Purpose of the Study:
- To identify molecular signatures associated with severe COVID-19 using proteomic and metabolomic analyses.
- To elucidate the role of specific biological pathways in COVID-19 pathogenesis.
Main Methods:
- Mass-spectrometry-based label-free proteomic analysis of plasma samples from COVID-19 patients.
- Metabolomic analysis to identify dysregulated metabolites.
- Validation of identified proteins using multiple reaction monitoring (MRM) assays.
- Integrated pathway analysis of proteomic and metabolomic data.
Main Results:
- Identification of approximately 10 significant proteins, 32 peptides, and 5 dysregulated metabolites in severe COVID-19.
- Validation of key proteins through MRM assays.
- Pathway analysis revealed significant alterations in complement and coagulation cascades, platelet aggregation, myeloid leukocyte activation, and arginine metabolism.
Conclusions:
- Leukocyte activation and arginine metabolism are implicated in the pathogenesis of severe COVID-19.
- Targeting these pathways presents a potential therapeutic strategy for COVID-19 treatment.
Abstract:
Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific molecular signatures associated with the elevated immune response are yet to be elucidated. We performed a mass-spectrometry-based proteomic and metabolomic analysis of COVID-19 plasma samples collected at two time points. Using Orbitrap Fusion LC-MS/MS-based label-free proteomic analysis, we identified around 10 significant proteins, 32 significant peptides, and 5 metabolites that were dysregulated at the severe time points. Few of these proteins identified by quantitative proteomics were validated using the multiple reaction monitoring (MRM) assay. Integrated pathway analysis using distinct proteomic and metabolomic signatures revealed alterations in complement and coagulation cascade, platelet aggregation, myeloid leukocyte activation pathway, and arginine metabolism. Further, we highlight the role of leukocyte activation and arginine metabolism in COVID-19 pathogenesis and targeting these pathways for COVID-19 therapeutics.
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