Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients. — CFSMEATLAS
Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients.
Shahbaz, Shima, Rezaeifar, Maryam, Syed, Hussein et al. · Brain, behavior, and immunity · 2025 · DOI
Quick Summary
Researchers studied blood samples from Long COVID patients with ME/CFS-like symptoms and compared them to healthy controls. They found that certain genes related to immune function and brain health were turned on in the patients, while others were turned off. The study also discovered unusual activation of smell-related genes and changes in immune cell types, suggesting the body remains in a state of ongoing inflammation and stress.
Why It Matters
This study identifies potential biomarkers (particularly RELN and immune cell alterations) that could improve LC/ME/CFS diagnosis and monitoring. The comprehensive gene expression profile provides mechanistic insights into how persistent immune dysregulation and neuroinflammation may drive long-term symptoms, informing future therapeutic target development.
Observed Findings
Upregulation of neuroinflammatory genes (RELN, Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3) in LC patients compared to controls
Altered immune cell composition: increased activated memory CD4+ T cells and neutrophils; decreased regulatory T cells and NK cells
Unexpected upregulation of olfactory receptor genes in whole blood, suggesting non-canonical functions outside olfactory tissue
Downregulation of pathways involved in tissue repair (VEGF signaling, TP53 activity) and cellular stress responses
Upregulation of metabolic and immune demand pathways (ribosomal RNA processing, amino acid metabolism, mitochondrial function, DNA repair)
Inferred Conclusions
Long COVID with ME/CFS phenotype involves complex dysregulation affecting both immune and neuronal systems, maintained at least 12 months post-infection
RELIN protein elevation may serve as a biomarker for LC pathogenesis due to its roles in inflammation and neuronal function
The chronic inflammatory immune state combined with impaired tissue repair mechanisms suggests sustained pathophysiological dysfunction
Olfactory receptors may have alternative immune or metabolic roles in non-olfactory tissues during Long COVID disease
Remaining Questions
What This Study Does Not Prove
This study does not prove that the observed gene changes cause ME/CFS symptoms—only that they are associated with the condition. It cannot establish whether these changes are primary drivers of disease or secondary consequences of infection. The findings require functional validation and longitudinal studies to determine causality and clinical relevance.