Title: Investigating Shiga toxin-induced endothelial glycocalyx dysfunction as a potential therapeutic target in Haemolytic Uraemic Syndrome
Funder: The Academy of Medical Sciences

Abstract: Background: Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that has a predilection to present in the kidney. It is a triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In 90% of cases, HUS follows gastroenteritis secondary to infection with Shiga toxin (Stx) producing bacteria such as Escherichia coli. Stx HUS is the leading cause of acute kidney injury in children with a mortality of 5%. The precise pathophysiological mechanisms following Stx infection leading to TMA are poorly understood. Our work has recently identified that the podocyte is capable of causing Stx HUS through terminal complement activation on glomerular endothelium. This project will investigate the mechanism behind this observation and whether Stx induces GEnC glycocalyx changes to impair complement Factor H (CFH) binding at the cell surface, resulting in loss of protection against complement attack culminating in glomerular TMA. Research Objectives: 1.Prove that Stx binding to podocytes affects GEnC glycocalyx integrity. 2.Demonstrate that Stx induced changes in GEnC glycocalyx lead to loss of CFH protection and development of TMA. 3.Investigate the effect of selectin inhibition in an animal model of Stx-HUS as a potential therapeutic agent in treatment of the disease. Justification: Through the application of rigorous and well established experimental techniques, this project will provide new insights into the glomerular mechanisms underlying Stx HUS. As such it has great promise to lead to the development of novel therapeutic targets to help patients, not only with Stx HUS but other complement-mediated glomerulopathies.

Lay abstract: Infection-associated haemolytic uraemic syndrome (HUS) represents a major public health issue as it is caused by infection with Escherichia coli (E.coli) entering the food chain. Infection-associated HUS is the commonest cause of kidney failure in children with 1 in 20 children dying. In adults, a more severe outcome is often observed with long-term kidney damage and a mortality of up to 12%. Currently, there are no specific treatments available for the condition. Our work suggests that following infection with E.coli, interaction between specialised cells in the kidney are responsible for over-activity of the immune system. I will be investigating how this leads to the development of the disease through the use of human kidney cell models and through an already established transgenic mouse model of Stx HUS. I am particularly excited by the potential of this work to provide new insights in to the mechanisms underlying Shiga toxin HUS and its promise to lead to novel treatments for patients with glomerular disease. In fact, the reason I first became interested in studying Shiga toxin HUS was after treating a a patient with severe disease, for whom we had no specific treatment and required multi-organ support on the intensive care unit. Built into this project is a clear research question with an emphasis on translation into clinical practice, which is very important to me as a scientist who is also a doctor looking after patients with kidney disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL