Understanding and manipulating innate-like B cell mechanisms to prevent stroke-associated infection

Stroke can cause considerable damage to the brain and is one of the most common causes of death and disability. Outcome and recovery after stroke are influenced not only by the brain damage but also by other complications happening inside and outside the brain. The most frequent complication of stroke that reduces the chances of a good recovery is infection, particularly from bacteria causing pneumonia in the lungs, which normally occurs in the first few days after stroke. At the moment, there are no treatments that are effective at reducing stroke-associated infection.

It is not fully understood why stroke patients are at such high risk of infection although several factors are probably involved. Research we and others have carried out previously suggests one of these contributing factors is that stroke causes some functions of the immune system that normally protect us from infection to stop working. If we can find out more about what aspects of protective immune function are affected by stroke, their causes, and ways to prevent or overcome these changes, we may be able to prevent or reduce the risk and poor impact of stroke-associated infection.

B cells are important immune cells that produce antibodies to help find and kill bacteria. If the number of B cells in our body is too low or they do not function properly this often leads to a much greater risk of infection. Some types of B cell, called innate-like B cells, produce antibodies very quickly and are essential for early defence against infection. Our recent work in a mouse model of stroke has shown that stroke causes a huge loss of these B cells in the spleen and impairs anti-bacterial functions normally performed by these B cells. We have also found that levels of antibody produced by these B cells are lower in stroke patients compared to healthy individuals.

The overall aim of our research project is to understand the scale of the disruption to innate-like B cells in different tissues throughout the body after stroke, their consequences on anti-bacterial immune function, and the signals involved in causing them. We will also test if a treatment we think can overcome disruption to these B cells can protect from stroke-associated infection.

We expect this work will show how badly innate-like B cells are affected after stroke and if targeting functions normally carried out by these cells to protect from infection may be a promising strategy for treatment of stroke patients. Ultimately, if results are positive, we hope the work will be a platform to set up trials in patients to further develop this treatment approach and test if it can reduce infection, disability and death in stroke patients.

Stroke-associated infection (SAI) is the most common complication of stroke, affecting up to one third of patients, and is independently associated with poorer short- and long-term outcome. Most infections occur early after stroke (50% within 2 d of onset) and bacterial pneumonia is the single most important cause of SAI. Currently, there are no effective treatments to prevent SAI and improve stroke outcome.

Growing evidence suggests stroke-induced impairments in systemic anti-microbial immune function as a contributing factor to the high risk of infection in stroke patients. Our recent data have shown for the first time the potential importance to SAI of compromised systemic innate-like B cell immunity induced by stroke. We found that experimental stroke in mice induced rapid loss of splenic marginal zone B cells, impaired MZ antigen capture and suppressed circulating IgM levels. A similar IgM suppression was observed in stroke patients.

Innate-like B cells comprise several subsets of B cells with molecular and functional characteristics of innate immune cells. They respond rapidly to infection and are particularly important for defence against opportunistic bacteria that cause pneumonia, in part through production of polyreactive IgM. Deficits in innate-like B cell function could be a particularly relevant mechanism in susceptibility to SAI.

In this project, our objectives are to take our previous work further to identify the scale of stroke-induced innate-like B cell changes, define mechanisms and consequences of these changes and, in a proof-of-concept experimental approach, test if targeting anti-microbial function regulated by innate-like B cells can reduce susceptibility to SAI. We expect this work will show the translational potential for targeting innate-like B cell-directed mechanisms to prevent SAI in patients. Ultimately, we aim to use this work as a platform to progress to future trials in humans.

We anticipate a number of beneficiaries of the proposed research including academic research communities, universities, clinical/healthcare groups, industry, schools, policy/advisory bodies and the general public.

Academic research community - we expect multiple groups will benefit including those in the stroke, immunology, infectious disease and translational science fields. These groups include those in the UK and internationally and include our collaborators. These groups will benefit through the increased knowledge and understanding our research will bring that will impact on their own ability to make advances in understanding related biological mechanisms, disease processes and through providing information to advance the development and refinement of reagents, tools and methodologies. The general biomedical community will also benefit through our training of researchers in highly skilled and sought-after techniques..

University teaching and education - our research findings will inform teaching and training content and practices by providing up-to-date information on scientific advances leading to a more relevant teaching experience equipping students with better knowledge and skills on current research, techniques and opportunities for career development. Of note, undergraduate and postgraduate students will benefit from exposure to this advancing knowledge environment while undertaking lab placements and postgraduate research degrees.

Clinical/healthcare - our project will benefit clinicians and healthcare professionals through advancing knowledge on potential new strategies for treatment and management of stroke and related neurological disorders. These groups would be able to use the data we generate to inform decisions on testing agents in clinical trials in patients. Our project may also impact on general policy and practice in the long-term through generating new concepts on how stroke patients can be treated and managed e.g. by targeting mechanisms outside the brain.

Industry - a key aim of our proposal is to generate an evidence base for a new therapeutic strategy and target for stroke. This information could be of interest to industry by informing their drug discovery and development pathways. Reciprocal benefits are possible through partnerships with industry and investment by companies in academia

Schools - through our research projects and engagement activities we are able to promote the awareness of how scientific research contributes to addressing important issues related to health and wellbeing.This can benefit schools through enriching the science curriculum and providing opinion and advice to pupils and teachers on careers in biomedical research

General public - our proposed research has the potential to impact on the health and well-being of the general population through identifying new ways to treat many more individuals affected by stroke and related neurological conditions. We are realistic to recognise this is a longer-term goal and that this benefit may take years to realise however our research has the potential to contribute a vital step in this process. Our research will also generate opportunities to increase public awareness of science and its role in reducing suffering associated with injury and disease. Stroke-associated infection is a poorly recognised aspect of major importance to how patients recover from stroke therefore increasing public awareness of this complication and research efforts to address this is vital. Similarly, there will be opportunities to increase public awareness of the role that animal models play in biomedical research.

Policy/advisory bodies - our work involves considerable use of in vivo approaches so has potential to generate new information influencing policy and practice relating to the use of animals in research. BM and SA are currently members of the NC3Rs Stroke Working Group.