How does the immune system respond to SARS-CoV-2 on a molecular and cellular level and what happens when the immune system overreacts?
Theme Lead: Professor Paul Kaye, Professor of Immunology at the University of York
This theme seeks to identify pathways by which immunopathology is mediated in COVID-19 in order to build on the recent observation that dexamethasone is a valuable mediation in this setting. Attempts so far to investigate mechanisms of immunopathology have been limited by the need to study tissue samples collected from patients during their disease and, in the case of a fatal outcome disease, at post-mortem.
These samples are often difficult to collect and individual collections may be insufficient to draw robust conclusions about the mechanisms of tissue damage. In addition, not all research centres have access to or expertise in the full breadth of modern molecular tools required to extract the most information from these samples. By pooling the resources of the centres and researchers across UK-CIC, a larger collection of samples can be made available and analysed in greater detail.
There are two key goals within this research theme:
1. To use up-to-date molecular analysis on tissue samples (biopsy or post-mortem) and assess whether it is the virus replicating and destroying cells or the immune system itself, that is more important
Patients with severe COVID-19 largely tend to suffer from significant inflammation and tissue damage, notably in the lungs but also affecting the heart, kidneys and other tissues. Although some of this damage is likely caused directly by virus infection, much of the observed tissue damage in affected organs is found in locations where virus is not detectable. Researchers are therefore working to understand how this damage is caused by the immune reaction to the virus.
By understanding the types of immune over-reaction, whether they are the same in all patient groups, and the cellular and molecular pathways that lead to this immunopathology, we may be able to find new drugs targets or repurpose existing drugs to selectively dampen or prevent tissue damage and improve patient outcomes. UK-CIC researchers are amongst the first in Europe to have adopted many new technological advances in molecular pathology that will allow them to investigate this problem in greater depth than before.
2. To assess the relative impact of two different parts of the immune system on tissue damage: the complement pathway and antibody-mediated immunopathology
In addition the studying the cellular arm of immunity, researchers will work to understand how soluble factors (antibodies, complement) contribute to tissue damage in severe COVID-19. Complement and antibody are known to cause tissue damage and regulate inflammation in many diseases but this is still poorly studied in COVID-19.
Working with the HICC consortium, UK-CIC researchers will look for biological markers associated with complement activation in blood or tissues that might predict or be causative for severe COVID-19 disease. Finding such biomarkers will help validate the complement pathway as an important therapeutic target in COVID-19.
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