Necroptosis and Cellular Stress Characterize Immune and Endothelial Dysfunction in Long COVID.

Publication date: Jul 23, 2026

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. 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. 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). 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. 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.

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