In-depth profiling of the long-term effects of SARS-CoV-2 infection

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with long-term consequences extending beyond acute illness. A significant proportion of individuals develop prolonged symptoms and persistent organ damage, collectively termed long COVID. Improving our mechanistic understanding of these sequalae is essential for developing effective monitoring strategies and targeted therapies. This thesis integrates a multi-modal approach to investigate the immunopathological mechanisms underlying both persistent symptoms and residual lung abnormalities (RLAs) in long COVID. Methods: A systematic review and meta-analysis of published biomarkers associated with long COVID was first conducted. Next, high throughput plasma proteomic profiling was performed on a well-characterised post-COVID cohort to identify molecular signatures in individuals with RLAs and persistent symptoms. Finally, single-cell RNA sequencing (scRNA-seq) was applied to bronchoalveolar lavage fluid from patients with early and late RLAs to characterise the immune landscape and identify pathways associated with resolution or persistence of lung injury. Results: The systematic review identified consistently elevated inflammatory markers in long COVID, particularly C-reactive protein (CRP) and interleukin-6 (IL-6). Proteomic analysis revealed that RLAs are characterised by proteins involved in B cell activation, extracellular matrix remodeling and tissue repair, while persistent symptoms were associated with dysregulated lipid metabolism and ongoing inflammatory responses. scRNA-seq analysis provided a granular map of immune cell populations and transcriptional profiles within the alveolar space, revealing evidence of dysregulated T cell populations, with potential therapeutic implications for modulating inflammation and limiting fibrotic progression. Conclusion: Together, these data demonstrate that persistent inflammation, immune dysregulation and aberrant tissue repair are central to long COVID pathophysiology. While SARS-CoV-2 infection causes sustained pulmonary injury in some individuals, it does not appear to model progressive fibrotic interstitial lung disease as initially feared. Ongoing efforts to identify and validate biomarkers will be critical for guiding disease monitoring and therapeutic development.