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Necroptosis and cellular stress characterize immune and endothelial dysfunction in long COVID
Carolina Carvalho Dias1, Jose Manuel Condor Capcha1, Emely Robleto1
1Division of Cardiology, Department of Medicine, University of Miami, Miami, Fla; Interdisciplinary Stem Cell Institute, University of Miami, Miami, Fla.
The Journal of Allergy and Clinical Immunology
|July 23, 2026
Summary
Long COVID involves persistent inflammation and cell stress, particularly necroptosis and autophagy, in immune and endothelial cells. These mechanisms contribute to chronic vascular and autonomic issues in survivors, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Cellular Biology
- Pathophysiology
Background:
- Long COVID (Post-Acute Sequelae of SARS-CoV-2 infection) presents persistent symptoms like fatigue and dysautonomia.
- The underlying cellular mechanisms of Long COVID remain poorly understood.
Purpose of the Study:
- To investigate immune and endothelial cell dysfunction in Long COVID patients.
- Focus on cell stress and death pathways, including necroptosis and autophagy.
Main Methods:
- Cross-sectional study comparing Long COVID patients (n=73) with matched controls (n=41).
- Clinical assessments: C19-YRSm, COMPASS-31, HRV, VRI.
- Flow cytometry analyzed immune cells and circulating endothelial cells (CECs) for markers of necroptosis (pMLKL), autophagy (LC3), and NETs.
Main Results:
- Long COVID patients exhibited higher symptom scores, impaired HRV, and endothelial reactivity.
- Increased pMLKL and LC3 expression observed in monocytes, neutrophils, and eosinophils.
- Elevated CECs showed activated necroptosis and autophagy, with increased monocyte-platelet and CEC-platelet aggregates, indicating a prothrombotic state.
Conclusions:
- Long COVID is characterized by persistent inflammation and endothelial stress via necroptosis and autophagy pathways.
- These cellular mechanisms may drive chronic vascular and autonomic dysfunction.
- Targeting these pathways offers potential therapeutic strategies for Long COVID.
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