University of Warwick Projects

ATB22-06 - Identification of biomarkers for chronic staphylococcal bone infections

Infection of the prosthetic joints is a serious complication after arthroplasty. This infection is frequently associated with the bacterial pathogen Staphylococcus aureus. Prosthetic joint infections, particularly chronic infections, are extremely challenging to eradicate due to ineffective bacterial killing using standard therapies. Diagnosis of chronic infections require invasive biopsies and imaging, and it is hard to determine the causative organism as routine methods are often unreliable. The pathogen S. aureus has several mechanisms by which it evades both antibiotics and our immune responses. In addition to its ability to form robust bacterial communities or biofilms, it is adept at invading bone cells, where it multiplies and survives during an infection. Intracellular bacteria are protected from antibiotic and immune responses. Standard culturing methods are not very effective for detecting such bacteria from chronic infections. The goal of this project is to combine laboratory infection models and molecular sequencing methodologies to determine bacterial and host markers that are distinct to chronic prosthetic joint infections. We seek to identify new markers that will help accurately diagnose chronic prosthetic joint infections.

ATB22-10 - Exploring unconventional tissue resident T cell immunity

Therapeutic interventions that harness the power of the immune system to destroy patients' cancers are emerging as the next frontier to tackle these deadly diseases. Human T lymphocytes (T cells) are vital to killing cancerous cells and form the basis for new therapeutic treatments. T cells expressing a gamma delta T cell receptor (gdTCR) are a poorly understood component of the immune system. However, they are highly represented in solid tissues and their infiltration into tumours has been identified as the single most important immunological feature of patients who survive a range of cancers. Moreover, due to the key positioning of gamma delta T cells in almost all solid tissues they are thought to play a critical role in the immune system’s ability to monitor tissues and organs for the emergence of cancerous cells.

Gamma delta T cells can respond and react to characteristic molecules produced when tissues turn cancerous, however the way they control and kill cancer cells remains unknown. We hypothesise that gamma delta T cell recognise cancer cells and tumours through their unique gamma delta TCR.

ATB23-06 - Investigating the expression and function of Isthmin-1 and asprosin in human placenta

Maternal obesity carries an increased risk of pregnancy-related cardio-metabolic complications that increase the risk of adverse outcomes for both the mother and offspring throughout gestation, labour and even into later life. With the increasing prevalence of obesity on a global scale, comes the increasing number of pregnancies affected by cardio-metabolic complications such as gestational diabetes mellitus (GDM) and preeclampsia.

The underlying cause of many of these pregnancy complications has not yet been fully clarified. Obesity results from accumulation of excess fat in the body. Fat cells secret/release proteins known as adipokines. Many adipokines and their specific receptors are expressed in the placenta and are involved in the development of maternal insulin resistance for the purpose of foetal growth and support. Furthermore, studies have investigated the expression of various adipokines in healthy pregnancy versus pregnancy associated with metabolic complications.

Asprosin and Isthmin-1 are novel adipokines secreted by the fat cells with opposite functions. Asprosin is an orexigenic peptide, with increased levels in obesity-related pregnancy complications such as GDM and preeclampsia, whilst Isthmin-1 is a is known to regulate sugar uptake while suppressing lipid accumulation. In this primary study, we are aiming to investigate the expression and function of these adipokines in placental tissue from normal pregnancies as well as pregnancies complicated with GDM and preeclampsia. Additionally, we aim to establish the molecular basis of biomarker release in preeclamptic patients, via the development of placental tissue in vitro cellular models.

ATB24-21 - Dissecting Clostridioides difficile-host-commensal interactions at the gut interface

The complex environment in our guts deters harmful bacteria called pathogens, from establishing an infection. When pathogens enter the gut, the pathogen, the healthy gut microbes (microbiota) and our gut cells engage in a three-way communication, which determines if the infection is successful. However, this three-way interplay remains elusive at a molecular level for many intestinal pathogens. This is mainly due to a lack of human gut models that allow bacterial interaction studies. Clostridioides difficile is a major gastrointestinal pathogen that causes C. difficile infection (CDI), a severe hospital-associated diarrhoea.

Our goal is to understand molecular pathways underpinning C. difficile-gut-microbiota interactions. Employing unique tools that we recently developed, we will define new pathways crucial for C. difficile survival in our guts. Three-way interactions of this pathogen will be investigated using an innovative colon-on-a-chip device with ‘engineered’ microbiota communities which will be developed using human colon tissue. State-of- the-art sequencing methods will also be used to study single-cell bacterial and colon cell responses during CDI. We anticipate this research to reveal unprecedented insight into the gut-microbial interface and novel pathways controlling infection, which will enable new therapeutic strategies to combat CDI and other gut infections.

ATB23-08 - Phage-based detection of Escherichia coli infections

Escherichia coli causes are range of disease including urinary tract infections, bacteremia, sepsis, and neonatal meningitis. While many of these infections can be life threatening, the rise of antibiotic-resistant E. coli isolates means that the treatment options for these infections is becoming increasingly limited. Delays in diagnosis can lead to poor clinical outcomes.

We propose to engineer “bioluminescent” phages against Escherichia coli clinical isolates which will transduce bioluminescence in the presence of the pathogens. In collaboration with Fixed Phage Ltd, we will develop a simple photodiode-based sensing platform to be used for the detection of bacterial infection in real patients’ samples, provided by Dr Evangelos Vryonis from UCHW, via the measurement of the bioluminescence intensity. Our long term is plan is the development of a bacterial infection sensor for point-of-care diagnosis.