Mawer, Connar Michael Alan; (2025) Investigation of the pathomechanisms underlying the development of post-COVID-19 residual lung abnormalities. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected over 778 million people globally and can lead to severe pulmonary complications. A subset of individuals develop post-COVID-19 residual lung abnormalities (RLAs), characterised by persistent fibro-inflammatory changes detectable on computed tomography (CT) scans, which have been reported to persist for months to years following hospitalisation for COVID-19. This study investigated the fibrotic potential of bronchoalveolar lavage fluid (BALF) from post-COVID-19 RLA patients compared with idiopathic pulmonary fibrosis (IPF) patients and healthy controls. BALF from post-COVID-19 RLAs induced significant fibroblast proliferation, differentiation into myofibroblasts, and collagen type I deposition, comparable to IPF-derived BALF. The receptor tyrosine kinase inhibitor nintedanib mitigated BALF-induced fibroproliferation, suggesting receptor tyrosine kinase ligands as key mediators. Investigation of SARS-CoV-2-infected nasal epithelial cells revealed minimal fibrogenic signalling within the basolateral secretome. However, the SARS-CoV-2 accessory protein ORF8, in combination with the pro-inflammatory cytokine IL-1β, enhanced the expression of fibrotic markers in organoid-associated fibroblast populations. These findings suggest a potential pro-fibrotic modulation of epithelial–mesenchymal crosstalk relevant to the acute phase of SARS-CoV-2 infection. These findings underscore fibroproliferative mechanisms underlying post-COVID-19 RLAs and support the therapeutic potential of receptor tyrosine kinase inhibition to mitigate fibrotic risk. Further investigation into the roles of viral proteins and epithelial-mesenchymal interactions may elucidate mechanisms driving pro-fibrotic signalling during acute SARS-CoV-2 infection, which could establish a pathological niche conducive to the development of fibrotic changes observed in post-COVID-19 RLAs.

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