Long COVID Linked to Persistent Immune Cell Stress

LONG COVID was associated with persistent immune and endothelial dysfunction, with evidence of increased necroptosis and autophagy that may contribute to chronic symptoms, according to a cross sectional study. 

Long COVID, also known as Post Acute Sequelae of SARS CoV 2 infection, affects a substantial proportion of people following SARS CoV 2 infection and is associated with persistent fatigue, dysautonomia, and cardiovascular complications. Although these long term manifestations are well recognised, the cellular mechanisms underlying ongoing disease remain incompletely understood. Researchers therefore investigated immune cell and endothelial dysfunction in adults with Long COVID, focusing on pathways involved in cellular stress and programmed cell death. 

The study enrolled 73 adults who met World Health Organization criteria for Long COVID and 41 age and sex matched participants who had recovered from SARS CoV 2 infection without persistent symptoms. Clinical assessments included Long COVID symptom severity, autonomic function, heart rate variability, and endothelial function. Peripheral blood samples were analysed using spectral flow cytometry to characterise immune cell populations and circulating endothelial cells. 

Necroptosis and Endothelial Stress Increased 

Participants with Long COVID reported significantly higher symptom scores than controls and demonstrated impaired heart rate variability together with reduced endothelial reactivity. 

Analysis of immune cells revealed increased expression of markers associated with necroptosis and autophagy, including phosphorylated mixed lineage kinase domain like protein and microtubule associated protein 1 light chain 3, in classical and non classical monocytes, neutrophils, and eosinophils. 

Circulating endothelial cells were also substantially increased in participants with Long COVID and demonstrated marked activation of necroptosis and autophagy pathways. Researchers additionally identified increased monocyte platelet and circulating endothelial cell platelet aggregates, findings that were consistent with a prothrombotic state. 

Importantly, elevated expression of phosphorylated mixed lineage kinase domain like protein in circulating endothelial cells strongly correlated with both Long COVID symptom severity and autonomic dysfunction. 

Potential Therapeutic Targets Identified 

The authors concluded that Long COVID was characterised by persistent inflammation and endothelial stress involving activation of necroptosis and autophagy pathways. These biological processes may contribute to chronic vascular dysfunction and autonomic impairment observed in affected individuals. 

They suggested that therapies targeting cellular stress and programmed cell death pathways may represent promising future treatment strategies for Long COVID. Further research will be needed to determine whether modulation of these mechanisms can reduce the long term consequences of SARS CoV 2 infection. 

Reference 

Dias C et al. Necroptosis and cellular stress characterize immune and endothelial dysfunction in Long COVID. J Allergy Clin Immunol. 2026;DOI: 10.1016/j.jaci.2026.06.026. 

Featured image: Beton Studio on Adobe Stock