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

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

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).

Technical Summary

The knowledge gap in COVID-19. The clinical, social and economic disruption caused by SARS-CoV-2 infection and its unpredictable progression to Acute Respiratory Distress Syndrome (ARDS) and chronic poor-health represents a global public health emergency. Emerging COVID-19 studies attribute pathogenesis to immune dysregulation, particularly implicating innate immunity to host tissue disruption. Severe lung pathology is associated with an aberrant inflammatory hyper-cytokine response, predominantly from myeloid cells (monocytes/macrophages). Age, gender, BMI and underlying medical conditions are risk factors, but there is a knowledge gap of host mechanisms that fail to restrain this aberrant response in acute-severe and long-term disease as compared with milder resolving disease. Our hypothesis is that myeloid cells from patients with severe and chronic COVID-19 have impaired endogenous homeostatic mechanisms that limit the pathogenic monocyte and lung macrophage activation in milder forms of disease.
Study protocol: (i) Longitudinal study of matched blood and lung lavage myeloid cells during the disease trajectories of moderate compared with severe COVID-19 with long-lasting ill-health. Single-cell phenotyping (transcriptome/proteome) will identify innate immune mechanisms determining acute and long-term pathogenesis and resolution. (ii) Ontogeny trajectory modelling of paired blood and lung lavage myeloid cells, in conjunction with epigenetic mapping (scATACseq) of identified pathways, will pinpoint monocyte drivers and biomarkers of acute and long-term pathogenic or resolving lung responses. (iii) An in vitro 2D and 3D model of human lung cell infection with SARS-CoV-2 will test the therapeutic potential of pathogenic and resolving pathways identified above.
Deliverables: Predicative myeloid biomarkers of acute and long-term COVID-19 severity, and therapeutic targets that could restrain aberrant pathogenic responses.

Publications

10 25 50
 
Description We uncovered the stages of macrophage activation driven by SARS-Cov2 infected epithelial cells using established by us 3D co-culture model and patient samples.. We also identified pathways that negatively regulate the development of cytokine storm in patients with mild COVID-19. This includes lambda interferon induced Protein S production by epithelial cells. Infected epithelial cell derived Protein S inhibits the activation of infiltrating pro-inflammatory macrophages and induce their phenotype switch to resolving macrophages in the lung of patients with mild COVID-19 and in co0culture model. In addition, we uncovered the pathogenic macrophage cluster associated with musculoskeletal symptoms of patients with long COVID-19.
Exploitation Route The most important discoveries that could in future inform treatment of patients with long COVID-19 is the discovery of the pathogenic macrophages clusters that are present in the joint of patients suffering joint symptoms in long COVID-19.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The discovery of common pathogenic macrophage clusters in severe COVID-19 and severe arthritis was selected for the journal front cover image (JCI_Insight), and highlighted in the August 2021 issue of 'JCI This Month'. The relevance to COVID-19 was highlighted in more than 80 national news outlets, including invitation for television interview.
First Year Of Impact 2021
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description synovial inflammation during long COVID-19 
Organisation Agostino Gemelli University Polyclinic
Country Italy 
Sector Hospitals 
PI Contribution Investigation of the cellular and molecular mechanisms of joint pain in patients suffering long COVID-19 using scRNASeq and functional assays
Collaborator Contribution recruitment of patients with long COVID-19 and collections of synovial biopsies
Impact presentations of discoveries at British Pharmacology Society Meeting September 2021 and EULAR2021
Start Year 2021
 
Description Invited lecture at British Society of Pharmacology 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact More than 100 people attend the event, the follow up dicussion indicated an increased interest in common targetable pathogenic mechanisms in lung and synovium
Year(s) Of Engagement Activity 2021
 
Description lay summary presentation of the discovery made on the grant at NRAS meeting (National Rheumatoid Arthritis Society) Scotland 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Around 100 patients with arthritis attended the event, and PhD students /researchers associated with PI group reported increased interest of Patient Partners group in their work.
Year(s) Of Engagement Activity 2021