Dissecting innate immune determinants of severity and resolution in a longitudinal study of COVID-19

The knowledge gap in COVID-19. Myeloid cells have a fundamental role in immune protection against infection. However, their powerful activity against pathogens is usually tightly regulated. This is because when this homeostatic control is deregulated, the over-activated myeloid cells can damage tissues, e.g. resulting in inflammatory joint diseases. Data emerging from the first wave of SARS-CoV-2 infection suggest that the catastrophic tissue damage following coronavirus infection can be attributed to over-activation of myeloid cells, resulting in hospitalisation with respiratory insufficiency and severe COVID-19. There is an urgent need for additional therapeutics to attenuate this progression of severity. With this project, we propose to address important and as-yet unanswered questions about the role of myeloid cells in severe COVID-19. These include: (i) Can we identify characteristics of myeloid cells at an early stage of SARS-CoV-2 infection that might help predict the clinical course of disease? (ii) What allows myeloid cells to escape the homeostatic regulation that would normally attenuate pathology? (iii) Can the regulatory mechanisms be reinstated? (iv) Do myeloid cells retain their aberrant activated state (epigenetics) and contribute to long-term post-COVID-19 symptoms (long-COVID-19)? Experimental plan. To address this knowledge gap, we will investigate the changes in myeloid cells in COVID-19 patients from the day of admission to hospital to post-COVID-19 phase at single cell resolution. Our specific plans include (i) investigating transient changes in their molecular pathways, particularly regulatory mechanisms that should switch-off activation. We will also explore (ii) whether SARS-CoV-2 infection induces long-lasting memory of aberrant activation (epigenetics) in myeloid cells and whether this contributes to long-COVID-19 pathologies. Expectation. We anticipate that our expertise in myeloid cell biology, experienced clinical monitoring and new technologies will discover new mechanisms by which myeloid cells contribute to progression or resolution of COVID-19 disease. From that knowledge we will identify myeloid cell characteristics (biomarkers) that can predict risk of developing severe and/or long COVID-19 and therapeutic targets for new drugs to prevent over-activation of myeloid cells during SARS-CoV-2 infection. The therapeutic potential of these discoveries will be tested in SARS-CoV-2 infected human lung 2D and 3D models in the laboratory. Team. To tackle these challenges, we gathered an international research team of scientists and clinicians with diverse and complementary expertise. These include expertise and facilities in: myeloid cell pathologies (Research into Inflammatory Arthritis Centre Versus Arthritis, RACE, University of Glasgow), COVID-19 (COVID-19 Academic Hospital, Fondazione Gemelli IRCCS, Rome, Italy), SARS-CoV-2 (Centre of Virus Research, University of Glasgow) and epigenetics (Institute of Cancer Sciences, University of Glasgow).