Our combined expertise in immunology in the Institute means we’re uniquely placed to understand how COVID-19 behaves and affects individuals.
One major area of focus within the Institute has been to longitudinally immuno-phenotype patient samples to understand the nature of the immune response to the SARS-CoV-2 virus which causes COVID-19.
In order to do this we formed the Coronavirus Immune Response and Clinical Outcomes (CIRCO) team with all major hospitals in Manchester.
So far our data has led to the key discovery that phenotypically and functionally abnormal monocytes (an immune cell released from the bone marrow) are an early-stage biomarker predictive of increased severity of disease.
In the future we plan to detect potential biomarkers for long COVID, look at whether the immune response varies in different patient groups and how age may affect the immune response to COVID-19.
Following the outbreak of the COVID-19 pandemic, the Institute rapidly established the Coronavirus Immune Response and Clinical Outcomes (CIRCO) study with all major hospitals in Manchester.
We quickly made a number of discoveries, which helped us to understand the coronavirus better and in turn led us to be able to propose new therapeutics and when people are more likely to benefit from receiving them.
Our work is unique in two ways:
- Hospitals gives us access to fresh samples for immune-phenotyping, meaning key information from the immune signature is not lost.
- Our study is longitudinal, meaning we can track patient outcomes to see a bigger picture.
How we did it
CIRCO has been a huge team effort with more than 100 researchers, clinicians and technicians working across the University, Manchester University NHS Foundation Trust, Salford Royal and Pennine Acute NHS Trusts.
Read this interview with Tracy Hussell, Director of the Lydia Becker Institute, on why Manchester was uniquely positioned to take on this challenge.
Without the effort of the people acknowledged here – from phlebotomists and nurses in the hospitals who took blood samples and consented patients to the researchers in the lab – our discoveries could not have happened.
Immunologists (The University of Manchester)
- Elizabeth Mann
- Madhvi Menon
- Joanne Konkel
- John Grainger
- Christopher Jagger
- Tovah Shaw
- Siddharth Krishnan
- Halima Ali Shuwa
- Nicholas A. Scott
- Alistair Chenery
- Mehwish Younas
- Kathryn Gray
- Saba Khan
- Emma Connelly
- Miriam Franklin
- Silvia Liu
- Christine Chew
- Flora A. McClure
- Barbora Salcman
- Oliver Brand
- David Morgan
- Ruth Stephens
- Verena Kaestele
- Thomas Williams
- Graham Lord
- Tracy Hussell
Northern Care Alliance (Salford Royal and Pennine Acute NHS Trusts)
- Sean Knight
- Nawar Bakerly
- Rob Oliver
- Seamus Grundy
- Alexander G. Mathioudakis
- Rohan Ahmed
- Emma Hardy
- Christina Parkinson
- Seema Sharma
- Evelyn Charsley
- Clare Moizer
- Paul Dark
- Andrew Ustianowski
- Laura Durrans
- Karen Connolly
- Jacinta Guerin
- Jade Harris
- Gabriella Lindergard
- Joanne Shaw
- Simon Dawson
Manchester Foundation Trust (MRI and Wythenshawe Hospital)
- Angela Simpson
- Timothy Felton
- Helen Francis
- Lesley Lowe
- Chantelle Hayes
- Rhys Tudge
- Gael Tavernier
- Lisa Willmore
- Joanne Mitchell
- Hannah Durrington
- Laurence Pearmain
- Katrina Moore
- Susannah Glasgow
- Jane Shaw
- Jasmine Egan
- Grace Padden
- Roanna Warren
- Stuart Moss
- Miriam Avery
- Anu John
- Pamela Hackney
- Katharine Birchall
- Lara Smith
- Richard Clark
- Ananya Saha
- Nicola Godfrey
- Simon Stephan
- Louis Wareing
- Bethany Jolly
- Elizabeth Shepley
Bioinformaticians (The University of Manchester)
- Magnus Rattray
- Mike Phuychareon
- Mudassar Iqbal
- Syed Murtuza Baker
NIHR Respiratory Translational Research Consortium
- Alex Horsley – Manchester Biomedical Research Centre (BRC)
- Tim Harrison – Nottingham BRC
- Joanna Porter – UCLH BRC
- Ratko Djukanovic – Southampton BRC
- Stefan Marciniak – Cambridge BRC
- Chris Brightling – Leicester BRC
- Ling-Pei Ho – Oxford BRC
- Lorcan McGarvey – Queen’s University Belfast
- Jane Davies- Imperial College BRC
- Marc Feldmann – University of Oxford
- Doreen Cantrell – University of Dundee
Explore a sample of current projects our members are working on.
Projects using the cohort of samples from the CIRCO study.
Investigating B and T cell responses in COVID-19 patients
T and B cells are types of white blood cell that play keys role in killing invading viruses by producing virus-specific antibodies, killing virus-infected cells and co-ordinating immune responses through the release of cytokines. In addition to their effector functions, regulatory B cells (Bregs) and regulatory T cells (Tregs) can also suppress the immune response, in order to prevent potentially harmful excessive inflammation during an infection.
Therefore, a balanced lymphocyte responses are important are vital to clear pathogens but also to restore immune homeostasis after an infection. We aim to understand how aberrant lymphocyte responses influence the clinical course of COVID-19 and how patients on existing immunotherapies and immune-suppression respond to infection.
Lymphocyte responses in long COVID
Long COVID has a diverse range of persistent symptoms. Therefore there is a compelling need to identify biomarkers for disease stratification and to develop personalised therapeutic strategies tailored to subsets of patients. Long-lasting B and T cell abnormalities in convalescent COVID-19 patients and their association with long COVID have not been explored previously. We aim to identify novel lymphocyte signatures that associate with specific clinical outcomes and provide an improved understanding of how B and T lymphocyte abnormalities contribute to long-term health issues.
Read the publication: Alterations in T and B cell function persist in convalescent COVID-19 patients
Immunoprofiling to stratify antibody responses to COVID-19 infection and vaccination
Antibody immunoprofiling is a technology which collects a ‘fingerprint’ of antibody binding characteristics using peptide microarrays. By training antibody immunoprofiles against clinical outcomes, we can use machine learning methods to train immunoprofile data.
The method could be used to compare antibody responses elicited by different vaccines to those from convalescent patients, and also those who tested positive for COVID-19 but exhibited few symptoms and presumably mounted an effective humoral immune response.
Clinical and immunological phenotypes of COVID-19
Sean Knight is the lead researcher for the COVID-19 tissue bank collection in the Northern Care Alliance.
During the pandemic the tissue bank has collected samples from more than one hundred patients admitted to their hospitals and have tracked changes in immunity over time, correlating these with key events in each patient’s journey.
This has led to several insights into how the immune system reacts in acute infection and how immunity changes on recovery.
We have expanded our collaborations to include several commercial and academic partners and as the national COVID-19 vaccination program gets underway, we will be looking at how historical health issues and recent infections influence immunity following vaccination.
Other research projects
As well as CIRCO, researchers within the Institute are working on a number of projects to understand the immunological basis of the SARS-CoV-2 virus.
IL-13 is a driver of COVID-19 severity
Tara Sutherland and Judi Allen (The University of Manchester) have been collaborating with the University of Virginia (UVA), Charlottesville, USA on a project related to the role of IL-13 in COVID-19.
Allie Donlan and Bill Petri from UVA found that elevated IL-13 was associated with the need for mechanical ventilation in two distinct UVA patient cohorts. Using a mouse model of SARS-CoV-2, Allie saw that blocking IL-13 reduced disease severity. At this point, Bill involved Judi and Tara in the study.
The role of IL-13 does not appear to follow traditional type 2 immune response profiles, but rather IL-13 leads to accumulation of hyaluronan in the lung. Blocking CD44, a hyaluronan receptor, also reduces disease severity. Tara, using autopsy samples from the University of Washington in Seattle, was able to confirm elevated hyaluronan in patients who have died from COVID-19.
Tony Day from the Wellcome Trust Centre for Cell Matrix Research is now involved in the study to provide essential hyaluronan expertise.
Remarkably, while this study was underway, we found that patients prescribed Dupilimab, which blocks the receptor for IL-4 and IL-13, had less severe disease. The work has revealed not only a potentially important pathway in COVID-19 but new roles for the type 2 immune response.
Read our pre-print article: IL-13 is a driver of COVID-19 severity
Protein biomarkers in COVID-19
The COVID-19 pandemic, has necessitated the urgent development of new diagnostic and therapeutic strategies. Research worldwide has moved rapidly to generate assays for detecting SARS-CoV-2 RNA and host immunoglobulins for diagnosis.
However, the complexities of COVID-19 are such that more complete definitions of patient status, outcomes, and the development of long-COVID are required.
There is accumulating evidence that protein biomarkers could help to provide this definition. In a recent review, we examined existing applications of proteomics to COVID-19 and SARS and outlined how pipelines involving technologies such as artificial intelligence could be of value for research on these diseases (Whetton et al., Journal of Proteome Research, 2020).
Proteins involved in the immune system and responses to inflammation are prominently observed in infectious diseases such as COVID-19. To address this particular issue, we examined data on immune modulators, cells, and disease associations captured from biological and medical literature associated with COVID-19, Coronavirus in general, SARS, and H5N1 influenza, with the objective of identifying potentially useful relationships and areas for future research (Geifman & Whetton, Journal of Translational Medicine, 2020).
We are currently developing an approach that can address the more general inflammatory signal that may be present in any proteomic biomarker signatures and identify a COVID-19 specific set of biomarkers that can better predict clinical outcomes.
We’re collaborating nationally and internationally to help create a better understanding of COVID-19.
We are leading one of the themes in the UK-CIC, a consortium of 19 immunology research centres investigating the immune response to SARS-CoV-2.
We are part of the NIHR Respiratory Translational Research Consortium.
Tracy Hussell sits on both the British Society for Immunology task force and the World Health Organisation Taskforce for Immune Therapeutics.
We are involved in PHOSP-COVID, a post-hospitalisation study looking at recovery.
With immunology a hot topic in the media, our researchers have been very active giving their expert commentary on a range of areas.
We’ve had more than 110 pieces of coverage in the last year.
See recent coverage and commentary:
- COVID-19 vaccines still induce a strong enough immune response (Dan Davis, The Times)
- Vaccine rollout in the UK (Dan Davis, LBC Radio)
- Will ultra-Orthodox Jewish communities hit herd immunity? (Tracy Hussell, Daily Mail)
- Alcohol-related deaths spiked during lockdown (Sheena Cruickshank, Daily Mail)
- Overcoming vaccine hesitancy (Tracy Hussell, BBC News)