Identifying the association between infection and MASLD progression and prognosis.

About the Project

Title: Identifying the association between infection and MASLD progression and prognosis.

Synopsis: Key questions (1) Are T lymphocytes of MASLD patients less functional than those of healthy controls? (2) Is there a preferential expansion of T cell clonotype in chronic disease which leads to varied MASLD prognosis? (3)What are the underlying cause of the preferential T cell clonotype expansion?

Details: Metabolic dysfunction-associated steatotic liver disease (MASLD) patients are characterised by increased fat deposition in the liver and a build-up of scar tissue. The microenvironment not only causes lipotoxicity to hepatocytes, but also influences the behaviour of local immune cells. MASLD patients have a significantly higher rate of severe infections compared to healthy people, suggesting the immune system plays an important role in MASLD progression and prognosis. However, MASLD is highly heterogenous with some patients progressing to a more severe form of disease and fibrosis such as MASH. It is unclear what are the underlying causes and mechanisms of this variability in disease progression. There is currently no cure for MASLD and no effective antifibrotic. This highlights the need for better understanding and disease stratification to develop a more efficient treatment.

We hypothesise that a shift in T-cell clonality during disease progression may contribute to the varied responses within patients and tolerance to disease progression. Fatty acids that accumulate in the liver cause T-cell dysfunction and disrupt T cell homeostasis, eventually making T cells less effective in clearing infectious agents. We aim to define the underlying mechanisms that contribute to the shift in the expanded T cell clones, specifically asking whether previous infections can lead to exacerbated MASLD pathogenesis by altering T cell clonality in the liver. We will isolate intrahepatic T cells from non-fatty, steatotic liver, and MASH livers and perform scRNA sequencing with TCR analysis to identify clonal shift of T cells during MASLD progression.

We will focus on a type of CD4+ T helper cell called regulatory T cells (Tregs). Tregs control the strength of immune response by suppressing other effector cell types to prevent overactivation. Tregs are essential for moderating the immune system and maintaining tissue tolerance. However, like much of the immune system, too much of a good thing can be damaging, and excessive Treg function can increase the risk of infections and cancer. We have shown that Tregs can be unstable in an injured microenvironment and become pro-inflammatory. This instability is caused by the factors and signals provided by surrounding cells. Tregs are known to acquire fatty acids from their environment and it is possible that Tregs behave differently when exposed to fatty acids, compared to other conventional T cells. We will explore the impact of MASLD-related fatty acids on Tregs and other conventional T cells to investigate whether this leads to impairment in T cell function and the clearance of infectious agent such as bacteria and viruses.

Besides the use of clinical (human) and murine T cells in vitro, we will also use transgenic mice to confirm whether a shift in T cell repertoire after infection will affect MASLD disease progression. Our mouse models of MASLD are well established and provide good insight into disease mechanism. Our combined (mouse & human) approach is rare and particularly powerful, enabling us to understand whether and how T cell clonality and dysfunction leads to increased progression towards incurable liver disease.

Potential impact: There is currently no cure for chronic liver disease such as MASLD, which affect around 30% of the world population. The output from this project has the potential to further stratify this highly heterogenous disease, and contribute to the development of treatment that targets MASLD with an “immune-related” signature.

Training: This project will use an exciting combination of human and murine models, with experimental approaches such as immune-organoid cultures and murine infections and analyses such as high dimension spectral flow cytometry and chemical and fluorescent tissue imaging. The combination of immunology, infection, cell biology and disease modelling will provide the student with a diverse range of skills relevant for academia, small enterprise, and pharmaceutical industry. Training will also include skill development in management, planning and supervision, providing an excellent foundation for many, varied careers.

Main techniques: Immune-Organoid culture, Multiplex Spectral flow cytometry, scRNA and TCR sequencing, Immunohistochemistry , Immunofluorescent staining, Human cell isolation.

Recruitment: BSc in biological sciences related subjects, MSc in immunology related subjects preferrable

Apply: All applications must be submitted through the Future Medicine PhD fellowships website.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.

The fellowships are open to students who are eligible for home fees at Edinburgh - i.e. you must be a UK national, or have settled status, and have. been "ordinarily resident" in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.