VacA mediated immunomodulation

The bacteria Helicobacter pylori (Hp) lives in the stomach, infecting 50% of the world's population. The majority of those infected do not suffer with any problems, but a small number develop ulcer disease and stomach cancers. Hp has infected the human population for 60,000 years. Over the last few decades, numbers of people infected have declined, and numbers of immune related diseases such as asthma and multiple sclerosis have increased.

We and others have done much research into an important bacterial protein, VacA, and shown that it not only influences a persons risk of developing gastric disease but also that it has an important impact on the immune system. It appears to manipulate the immune system to produce more regulatory immune cells. These cell types are important for preventing diseases such as Multiple Sclerosis. As there are many different types of VacA, this project aims to differentiate exactly which part of the vacA gene, and which type of VacA has the most dramatic effect on the immune system. This work will be important in order to encourage clinicians to consider all the potential implications when contemplating which patients require treatment for Hp to ensure that it is not wiped out in the human population. In the future, a molecule similar to VacA could potentially be employed as a therapy against Multiple Sclerosis.

Helicobacter pylori colonises 50% of the world's population and is associated with a variety of gastric diseases including adenocarcinoma. Having co-evolved with the human race over 60,000 years, Hp has adapted to manipulate the immune system to prevent clearance. Over the last few decades, the prevalence of Hp has reduced, whilst the prevalence of chronic immune-mediated diseases such as asthma and multiple sclerosis (MS) have dramatically increased. We and others have shown that the virulence factor VacA (vacuolating cytotoxin A) is an important driver of the immune response to Hp. Recent research has shown that it influences dendritic cell maturation, inducing a toleragenic state. We have shown that the vacA gene is always present but highly polymorphic, with these polymorphisms directly influencing activity. We hypothesise that the most active form of VacA will have the most significant immunomodulatory properties.

Objectives
1. To characterise the strength of tolerogenic activity of different VacA types on murine dendritic cells in vitro.
2. To characterise the effect of VacA on human monocyte-derived dendritic cells in vitro.
3. To investigate the role of VacA-mediated effects on murine immune responses in vivo and determine their impact in a mouse model of multiple sclerosis.
Design/Methodology
Murine bone marrow derived dendritic cells and human monocyte derived dendritic cells will be co-cultured with a panel of vacA mutants. Flow cytometry will be performed to evaluate maturation and activation. ELISA for specific cytokines will also be undertaken. Hp matured dendritic cells will then be cultured with naive T cells. Differentiation will be assessed by flow cytometry and cytokine ELISA. In vivo work will then be carried out in a mouse model of infection.
Scientific/Medical opportunities
This will provide a better understanding of the immune response to Hp and help explain why infection appears to be protective of certain immune mediated diseases.

Policy makers

The research will aim to educate government policy makers on the importance of infection, immunity and autoimmunity.

Industry

Those working in industry researching Multiple Sclerosis are likely to benefit from my work, the results of which will help inform further research.

General public

The proposed research will promote greater public understanding of science through public engagement activities. The proposed research will show the public the benefits of animal research. I will participate in the Nottingham Digestive Diseases centre public engagement event as well as the university-wide community open-day, 'Mayfest'. I will undertake public engagement training in the university's graduate school.
The proposed research will promote research and science in schools, encouraging and inspiring a new generation of scientists.
I am currently a STEM ambassador, which involves work in schools promoting science based careers.

Economy

MS affects 2.5 million people worldwide. It is a disease which primarily affects young, working age people, and is the major cause of non-traumatic disability in young adults. This means it has a significant economic impact, costing the UK roughly £30,000 per person per year in loss of productivity, healthcare and costs to family.
We hope that this research will contribute significantly to the research into novel agents for the treatment of Multiple Sclerosis and ultimately have economic impact.

Multiple Sclerosis patients/family

Multiple Sclerosis can be a serious burden to an individual as well as that individual's family. As previously mentioned, it is the leading cause of non-traumatic disability in young adults. This leads to loss of earnings, independence and reduced life expectancy.

Patients infected with Helicobacter pylori

If this research fulfills our expectations it will raise the need for better risk stratification in the eradication of Helicobacter pylori, to avoid further increases in the prevalence of auto-immune and inflammatory disorders whilst preventing the occurrence of gastro-duodenal disease.