Structural Studies into E. coli SslE and its role in Diarrhoeal Diseases

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Bacteria are single cell organisms that inhabit a wide range of environments and can have both a positive and negative impact on human health. The gastrointestinal tract in humans is covered by a layer of mucus and this acts as a barrier to separate host cells from "good bacteria" but also from invading pathogens. However, dangerous bacteria have developed ways to bind and break down host mucus, which releases nutrients to help the bacteria grow but also allows them to access host tissues so they can bind and initiate infection. In this application, we propose a number of experiments that will help us to understand how some dangerous bacteria are able to cause disease in humans through interactions with mucus. We will specifically be studying Escherichia coli, which is commonly found in the human intestines and is often beneficial to the host. However, infectious strains cause severe diarrhoeal diseases, urinary tract infections, blood infections (sepsis) and meningitis. For example, enterotoxigenic E. coli (ETEC) is a strain which is responsible for up to 400 million cases of diarrhoea each year in the developing world, results in the death of at least 300,000 children and is the most frequent cause of traveller's diarrhoea.E. coli use a 'type II secretion system' (T2SS), a syringe-like mechanism to transport proteins into their surroundings and many of these secreted proteins help the bacteria to cause disease. One such protein, SslE, is secreted by many infectious and some beneficial E. coli strains. Once exported it can break down mucus in the intestines but also allows E. coli to form biofilms, where bacteria clump together and are protected from the local environment. In pathogenic strains, SslE has a major role in promoting bacterial disease. We have been studying SslE from both a harmless and an enterotoxigenic strain and we have begun to unravel how SslE is able to perform these two different functions. Understanding the details of how this protein functions and how it interacts with host mucus will be crucial to further our knowledge of E. coli infection in diarrhoeal and other diseases. Furthermore, this secreted protein has shown great promise as a target to develop new vaccines for a range of different types of disease-causing E. coli strains, so providing a better understanding here will also aid future vaccine development. These studies may also reveal common pathways for infectious disease used by other bacteria, which may in turn help us design compounds which disarm E. coli and other dangerous pathogens.