Investigation of the pathomechanisms underlying the development of Interstitial lung disease (ILD) in COVID-19

Recent radiographic evidence has linked COVID-19 pneumonia, caused by SARS-CoV-2, with persistent interstitial lung disease (ILD), including pulmonary fibrosis. High resolution imaging with computerised tomography is used as part of the diagnosis and management of ILD, as well as COVID-19-related pathology (Raghu et al., 2011; Rodrigues et al., 2020). Radiological assessment of acute COVID-19 pneumonia (weeks 1-4, from onset) show a proportion of patients have persistent ILD (Pan et al., 2020; Wang et al., 2020; Myall et al., 2021), while longer-term outcomes (months 1-12, from onset) show a proportion of patients have persistent ILD and changes consistent with fibrosis/fibrogenesis (Liu et al., 2021; Han et al., 2021; Wu et al., 2021).

Pulmonary fibrosis can be caused by repetitive injury, dysregulated inflammation, failure of re- epithelialisation (by alveolar epithelial stem cells) and excessive fibroblast proliferation/differentiation (Wuyts et al., 2013; Sgalla et al., 2018; Yim et al., 2021). While viral infections can cause pulmonary fibrosis, the mechanism is not fully understood (Naik and Moore, 2010; Molyneaux and Maher, 2013; Sheng et al., 2020; Fabbri et al., 2021). Furthermore, while there is speculation on the cellular contribution to post-COVID-19 related pulmonary fibrosis, the mechanism remains unclear (John et al., 2021). Although, emerging data has linked CD8+ T-cells with persistent ILD, up-to 6-months post-COVID-19 (Vijayakumar et al., 2021).

This project aims to understand why some COVID-19 patients recover, while others go on to develop persistent ILD, including fibrosis. We plan to profile the key cells involved in pulmonary fibrosis; fibroblasts, alveolar epithelial cells and immune cells.

Initial studies will focus on examining the fibrogenic potential of SARS-CoV-2 infection of the epithelium, including the ability of conditioned media released by infected epithelial cells to promote fibroblast proliferation and collagen deposition. The impact of alveolar regeneration will be examined using human lung organoid models, recently established in the host laboratory. In parallel studies, we will use single-cell RNA-seq of bronchoalveolar lavage samples to interrogate the immune profile of patients who went on to develop ILD, compared to those who resolved. Since COVID-19 persistent ILD is associated with age (Liu et al., 2021; Han et al., 2021; Wu et al., 2021), future studies will also explore the impact of senescence as a determinant of the development of ILD in these patients