Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

Shima Shahbaz; Maryam Rezaeifar; Hussein Syed; Desiree Redmond; Jan Willem Cohen Terveart; Mohammed Osman; Shokrollah Elahi

doi:10.1016/j.bbi.2024.11.032

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00721-9. doi: 10.1016/j.bbi.2024.11.032. Online ahead of print.

Authors

Shima Shahbaz¹, Maryam Rezaeifar¹, Hussein Syed², Desiree Redmond³, Jan Willem Cohen Terveart³, Mohammed Osman⁴, Shokrollah Elahi⁵

Affiliations

¹ Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada.
² Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton T6G 2E1, AB, Canada.
³ Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton T6G 2E1, AB, Canada.
⁴ Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Women and Children Health Research Institute, University of Alberta, Edmonton T6G 2E1, AB, Canada. Electronic address: mosman@ualberta.ca.
⁵ Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Women and Children Health Research Institute, University of Alberta, Edmonton T6G 2E1, AB, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2E1, AB, Canada; Glycomics Institute of Alberta, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, AB, Canada. Electronic address: elahi@ualberta.ca.

PMID: 39615603
DOI: 10.1016/j.bbi.2024.11.032

Abstract

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses. Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Keywords: Chronic fatigue syndrome; ME/CFS; RELN; Reelin; SARS-CoV-2.