Role of haptoglobin and its phenotypic variations in the pathophysiology of myalgic encephalomyelitis and long COVID
Atefeh Moezzi
Supervisor: Alain Moreau
Abstract
Myalgic encephalomyelitis (ME) and Long COVID (LC) are chronic, multisystem disorders characterized by post-exertional malaise (PEM), cognitive dysfunction, and marked interindividual variability in symptom severity. The molecular mechanisms underlying this heterogeneity remain incompletely understood.
Given the central role of oxidative stress, vascular dysregulation, and metabolic impairment in PEM, proteins involved in systemic redox and stress responses represent promising mechanistic candidates. Haptoglobin (Hp), a hemoglobin-binding protein involved in oxidative stress regulation and vascular homeostasis, may therefore represent a key modulator of post-exertional responses in both conditions.
Objectives
This thesis aims to investigate the role of Hp in ME and LC by characterizing its phenotypes and examining their associations with symptom severity, particularly PEM.
Methods
A prospective two-phase study was conducted in the ME cohort, combining plasma proteomic profiling, cognitive assessments, and Hp phenotyping and proteoform analysis in response to a standardized exertional stress protocol, using high performance liquid chromatography (HPLC).
In the LC cohort, a longitudinal observational study integrated Hp phenotyping with clinical questionnaires, cognitive testing, plasma metabolomics, and cerebral oxygenation measurements using near-infrared spectroscopy (NIRS) following a standardized PEM induction protocol, with additional follow-up assessments at 6 and 12 months.
Results
In ME, Hp levels decreased following exertional stress and were associated with cognitive performance. Hp phenotypes showed distinct clinical associations, with Hp2-1 linked to greater PEM severity and cognitive impairment, while Hp1-1 was associated with milder symptoms and greater cognitive resilience. Structural alterations in Hp proteoforms further supported phenotype-specific differences.
In LC, Hp phenotype was associated with differential symptom burden, metabolic responses, and cerebral oxygen utilization. Hp2 carriers exhibited greater fatigue, post-exertional cognitive decline, reduced metabolic intermediates, and impaired cerebral oxygen extraction compared to Hp1-1 individuals, who showed relative cognitive resilience and improved longitudinal outcomes.
Conclusion
Hp phenotype is associated with heterogeneous post-exertional responses in both ME and LC, suggesting a shared role in modulating oxidative stress, metabolic adaptation, and cerebral oxygenation.
These findings support Hp phenotypes as potential biomarkers for patient stratification and a mechanistic link underlying clinical heterogeneity in these two chronic debilitating conditions.
Web | DOI | PDF | University of Montreal | Thesis
Atefeh Moezzi
Supervisor: Alain Moreau
Abstract
Myalgic encephalomyelitis (ME) and Long COVID (LC) are chronic, multisystem disorders characterized by post-exertional malaise (PEM), cognitive dysfunction, and marked interindividual variability in symptom severity. The molecular mechanisms underlying this heterogeneity remain incompletely understood.
Given the central role of oxidative stress, vascular dysregulation, and metabolic impairment in PEM, proteins involved in systemic redox and stress responses represent promising mechanistic candidates. Haptoglobin (Hp), a hemoglobin-binding protein involved in oxidative stress regulation and vascular homeostasis, may therefore represent a key modulator of post-exertional responses in both conditions.
Objectives
This thesis aims to investigate the role of Hp in ME and LC by characterizing its phenotypes and examining their associations with symptom severity, particularly PEM.
Methods
A prospective two-phase study was conducted in the ME cohort, combining plasma proteomic profiling, cognitive assessments, and Hp phenotyping and proteoform analysis in response to a standardized exertional stress protocol, using high performance liquid chromatography (HPLC).
In the LC cohort, a longitudinal observational study integrated Hp phenotyping with clinical questionnaires, cognitive testing, plasma metabolomics, and cerebral oxygenation measurements using near-infrared spectroscopy (NIRS) following a standardized PEM induction protocol, with additional follow-up assessments at 6 and 12 months.
Results
In ME, Hp levels decreased following exertional stress and were associated with cognitive performance. Hp phenotypes showed distinct clinical associations, with Hp2-1 linked to greater PEM severity and cognitive impairment, while Hp1-1 was associated with milder symptoms and greater cognitive resilience. Structural alterations in Hp proteoforms further supported phenotype-specific differences.
In LC, Hp phenotype was associated with differential symptom burden, metabolic responses, and cerebral oxygen utilization. Hp2 carriers exhibited greater fatigue, post-exertional cognitive decline, reduced metabolic intermediates, and impaired cerebral oxygen extraction compared to Hp1-1 individuals, who showed relative cognitive resilience and improved longitudinal outcomes.
Conclusion
Hp phenotype is associated with heterogeneous post-exertional responses in both ME and LC, suggesting a shared role in modulating oxidative stress, metabolic adaptation, and cerebral oxygenation.
These findings support Hp phenotypes as potential biomarkers for patient stratification and a mechanistic link underlying clinical heterogeneity in these two chronic debilitating conditions.
Web | DOI | PDF | University of Montreal | Thesis