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Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and
Cristiana Iosef1, Michael J Knauer2, Michael Nicholson3
1Children's Health Research Institute, Victoria Research Laboratories, 800 Commissioners Road East, London, ON, N6C 2V5, Canada. cristiana.iosef@lhsc.on.ca.
Insights
Long-COVID involves a vasculo-proliferative process affecting natural killer cells and neutrophils, potentially leading to organ dysfunction. This study identified prognostic biomarkers and therapeutic targets for Long-COVID.
Area of Science:
- Immunology
- Vascular Biology
- Proteomics
Background:
- Long-COVID presents diverse, prolonged symptoms post-SARS-CoV-2 infection.
- Understanding Long-COVID mechanisms is crucial for prognosis and treatment.
Purpose of the Study:
- To investigate the underlying mechanisms of Long-COVID.
- To identify potential prognostic biomarkers and therapeutic targets.
Main Methods:
- Plasma proteome analysis using proximity extension assays on Long-COVID outpatients, COVID-19 inpatients, and healthy controls.
- Bioinformatics deconvolution of protein biomarkers into cell types, signaling pathways, and organ specificity.
- Validation of key markers (ANGPT1, VEGFA, etc.) using serological methods.
Main Results:
- Long-COVID patients exhibited natural killer cell redistribution and neutrophil extracellular traps.
- Vascular events involving angiopoietin-1 and vascular-endothelial growth factor-A were observed.
- Evidence of vascular inflammation, a proliferative state, and potential links to neurologic and cardiometabolic dysfunction.
Conclusions:
- A vasculo-proliferative process, potentially triggered by hypoxia or inflammatory factors, characterizes Long-COVID.
- Plasma proteome analysis revealed organ-specific prognostic biomarkers and therapeutic targets.
- Findings inform potential treatment strategies for Long-COVID.
Aims:
Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment.
Methods:
Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity.
Results:
Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction.
Conclusions:
Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.
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