
Our Career Enhancing Grants provide early career immunologists with flexible financial support to tackle challenges and move their career forward. In this article, BSI member Dr Damián Pérez-Mazliah explains how his grant helped him to unearth the extraordinary mechanisms by which pathogens alter our immune system to cause autoimmunity.
Investigating infection-driven autoimmunity
We all know our B cells as the white blood cells that produce antibodies to protect us from pathogens. But on rare occasions, some B cells – which we call autoreactive B cells – begin to produce antibodies that, instead of fighting infections, attack the body's own tissues. This leads to autoimmune diseases that can affect a variety of vital organs, with well-known examples including type 1 diabetes, rheumatoid arthritis, psoriasis and multiple sclerosis. It is estimated that one in ten people in the UK has an autoimmune condition, which equates to 6.7 million people.
Although the triggers for autoimmune disorders are diverse and, in many cases, unknown, we do know that some pathogens have the extraordinary capacity to alter our immune system, leading to malfunctioning and autoimmunity. Quite how they do this is still unclear. Funded by a Royal Society University Research Fellowship, my laboratory, based at the University of York and forming part of Hull York Medical School, is currently exploring the mechanisms that regulate infection-driven autoimmunity, with a particular focus on infection-driven heart disease.
Cardiovascular diseases are the leading cause of death globally. The immune system plays a key role in cardiac development, composition and function. Under certain circumstances, particularly in response to infection, immune cells can infiltrate the heart in large numbers to remove dying tissue, scavenge pathogens and promote healing. If left uncontrolled, these immune cells can go on to cause collateral tissue damage, leading to heart dysfunction and failure. Moreover, the heart can be directly affected by autoreactive B cells, resulting in damage to its structures.
My lab’s goal is to better understand how some B cells develop into the type that fight infections, while others become the type that attack the heart. In addition, we want to identify the cellular and molecular mechanisms through which autoreactive B cells contribute to heart tissue damage. In order to do so, we are currently using Trypanosoma cruzi as an infection model. T. cruzi is the protozoan parasite that causes Chagas disease (American trypanosomiasis), a major cause of infectious heart disease worldwide and the highest-impact parasitic disease in the western hemisphere. In response to T. cruzi infection/Chagas disease, and driven by triggers that remain poorly understood, the immune system produces both antibodies against the parasite and against the heart. Using a combination of cutting-edge molecular and cellular techniques, we have been able to establish that chronic T. cruzi infection leads to a large and very unusual accumulation of B cells in the heart.
Across the globe
My journey here has seen me take up roles with a number of key research institutes, and has brought me halfway across the globe. After completing my PhD on immunity to T. cruzi/Chagas disease, I relocated from Argentina, where I was born and educated, to the MRC National Institute for Medical Research in London. There I studied B cell immunity to the malaria-causing Plasmodium parasites in rodent models. Then, after completing my postdoc in 2018, I joined the flow cytometry science technology platform at the Francis Crick Institute, after which I moved to The Lancet to work as an editor for the journal eBioMedicine, part of The Lancet Discovery Science. It was in 2019 that I moved to the University of York, funded by Hull York Medical School, with the goal of starting my independent research programme and laboratory.
No mean feat
The transition from postdoctorate to independent group leader comes with a number of major challenges, to which I was not ‘immune’. You must demonstrate the capacity to lead a team and produce good quality research, while also carving out an innovative research niche, and this is no mean feat. I had joined the British Society for Immunology soon after moving to the UK, on the recommendation of my mentor Jean Langhorne, and the Society quickly became an important source of support for me. Perhaps the most critical support I have received from the BSI to date has been my Career Enhancing Grant. This was awarded during my recent endeavours to become an independent researcher, and allowed me to complement the funding provided by Hull York Medical School and complete a very costly proof-of-concept single-cell RNA sequencing (scRNA-seq) dataset.
Embracing single-cell RNA sequencing
scRNA-seq is a powerful genomic approach for detection and quantification of protein-encoding messenger RNA molecules on vast numbers of individual, isolated cells using next-generation sequencing. When I moved to York in 2019, scRNA-seq studies were expensive and had been conducted mostly by specialist research groups. Still, immunologists were already demonstrating the enormous potential of scRNA-seq for studying cellular diversity of immune responses, suggesting the technology was well on the way to becoming an essential tool for immunology research labs. Nonetheless, given the relative novelty and high costs of the approach, I needed to demonstrate to external funders that I was able to successfully apply this technology to answer my own research questions. While I had raised much of the cost for this study from internal sources and through in-kind contributions, there remained a shortfall associated with next-generation sequencing costs (very expensive at that time), which were eventually covered by the BSI Career Enhancing Grant.
Using scRNA-seq, we observed that development of Chagas heart disease was accompanied by a large accumulation of B cells with an unusual phenotype, both in secondary lymphoid organs as well as in the heart itself. These preliminary data prompted additional and extensive research, greatly strengthening my case for support, and were ultimately key to securing a University Research Fellowship from the Royal Society. This was the big step I needed to achieve my goal of starting my independent research programme.
Team goals
For the next five years, I will be leading a small and international team of three young researchers: Shazia Ashraf, Aleksandra Dąbek and Muhammad Asad Kamran. Our focus will be to study the nature of heart-resident B cells, how they interact with other types of heart-resident cells (fibroblasts, cardiomyocytes) and ultimately, whether and how they contribute to the development of heart fibrosis and dilated cardiomyopathy. We are motivated by the hope that our research may help to improve the quality of life of people affected by neglected tropical diseases and autoimmunity.
Dr Damián Pérez-Mazliah, Hull York Medical School, University of York
Find out how to apply for a Career Enhancing Grant here.