Chandelier
Senior Member (Voting Rights)
Necroptosis and Cellular Stress Characterize Immune and Endothelial Dysfunction in Long COVID
The cellular mechanisms underlying these chronic symptoms remain incompletely understood.
Clinical assessments included COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), Composite Autonomic Symptoms Score (COMPASS-31), heart rate variability (HRV), and vascular reactivity index (VRI).
Peripheral blood was analyzed by spectral flow cytometry to characterize immune cell and circulating endothelial cell (CEC) populations and their expression of markers related to necroptosis (pMLKL), autophagy (LC3), hypoxia (HIF1-1α), and neutrophil extracellular traps (MPO, CitH3, NE).
Flow cytometry revealed increased expression of pMLKL, and LC3 in classical and non-classical monocytes, neutrophils, and eosinophils.
CECs from Long COVID participants were substantially increased and demonstrated marked activation of necroptosis and autophagy pathways.
These findings were accompanied by increased monocyte–platelet and CEC–platelet aggregates, consistent with a prothrombotic state.
Elevated pMLKL expression in CECs strongly correlated with symptom severity and autonomic dysfunction.
These mechanisms may contribute to chronic vascular and autonomic dysfunction in Long COVID patients.
Targeting these stress and death signaling pathways may offer novel therapeutic strategies to mitigate the long-term consequences of SARS-CoV-2 infection.
Key Messages:
• Long COVID is characterized by persistent immune and endothelial cellular stress, with increased necroptosis and autophagy markers in monocytes, lymphocytes, and circulating endothelial cells.
• Endothelial pMLKL expression correlates with symptom severity and impaired vascular reactivity, supporting necroptosis-linked vascular injury as a clinically relevant feature of Long COVID.
Capsule Summary:
This study identifies necroptosis-linked immune and endothelial injury as a clinically relevant feature of Long COVID, associating vascular dysfunction, dysautonomia, and symptom severity with potential biomarker and therapeutic targets.
Web | DOI | Journal of Allergy and Clinical Immunology | Paywall
Dias, Carolina Carvalho; Condor Capcha, Jose Manuel; Robleto, Emely; Guevara, Patricia; Bast, Elizabeth; Palacio, Ana; Tamariz, Leonardo; Shehadeh, Lina A.
Abstract
Background
Long COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), affects a significant proportion of COVID-19 survivors and is associated with persistent fatigue, dysautonomia, and cardiovascular complications.The cellular mechanisms underlying these chronic symptoms remain incompletely understood.
Objective
Investigate immune and endothelial cell dysfunction, with a focus on cell stress and death pathways, in individuals with Long COVID compared to matched infection-recovered controls.Methods
We conducted a cross-sectional study at the University of Miami Miller School of Medicine and the Miami VA Healthcare System enrolling adults who met WHO criteria for Long COVID and age- and sex-matched controls with no history of Long COVID symptoms were recruited.Clinical assessments included COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), Composite Autonomic Symptoms Score (COMPASS-31), heart rate variability (HRV), and vascular reactivity index (VRI).
Peripheral blood was analyzed by spectral flow cytometry to characterize immune cell and circulating endothelial cell (CEC) populations and their expression of markers related to necroptosis (pMLKL), autophagy (LC3), hypoxia (HIF1-1α), and neutrophil extracellular traps (MPO, CitH3, NE).
Results
Long COVID patients (n=73) showed significantly higher Long COVID symptom scores compared to controls (n=41), along with impaired HRV and endothelial reactivity.Flow cytometry revealed increased expression of pMLKL, and LC3 in classical and non-classical monocytes, neutrophils, and eosinophils.
CECs from Long COVID participants were substantially increased and demonstrated marked activation of necroptosis and autophagy pathways.
These findings were accompanied by increased monocyte–platelet and CEC–platelet aggregates, consistent with a prothrombotic state.
Elevated pMLKL expression in CECs strongly correlated with symptom severity and autonomic dysfunction.
Conclusion
Our findings demonstrate that Long COVID is characterized by persistent inflammation and endothelial stress, involving necroptosis, and autophagy pathways.These mechanisms may contribute to chronic vascular and autonomic dysfunction in Long COVID patients.
Targeting these stress and death signaling pathways may offer novel therapeutic strategies to mitigate the long-term consequences of SARS-CoV-2 infection.
Key Messages:
• Long COVID is characterized by persistent immune and endothelial cellular stress, with increased necroptosis and autophagy markers in monocytes, lymphocytes, and circulating endothelial cells.
• Endothelial pMLKL expression correlates with symptom severity and impaired vascular reactivity, supporting necroptosis-linked vascular injury as a clinically relevant feature of Long COVID.
Capsule Summary:
This study identifies necroptosis-linked immune and endothelial injury as a clinically relevant feature of Long COVID, associating vascular dysfunction, dysautonomia, and symptom severity with potential biomarker and therapeutic targets.
Web | DOI | Journal of Allergy and Clinical Immunology | Paywall