Defining the mechanisms controlling mucus function

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Mucus is essential for health and this gel-like substance controls access of disease-causing microbes and harmful substances to cells and tissues at exposed mucosal surfaces of animals (for example, the linings of the lung and gut). It is therefore the critical first line of defence against infection, chemical challenges and physical injury. Far from being just a simple physical barrier, new evidence has revealed that mucus is complex and dynamic, and responsive to environmental challenges, such as those induced by disease-causing microbes. While great progress has been made towards understanding mucus function, we currently still lack the precise details of how mucus performs its vital protective role in maintaining healthy mucosal surfaces. Here, we will take a multi-pronged approach to discover how mucus properties are controlled to optimise its defensive role and how these properties evolve when fighting bacteria. The structural integrity and many of the known functional properties of mucus are due to a family of very large sugar-rich molecules called gel-forming mucins. These molecules underpin protective mucus barriers found throughout the animal kingdom, and of particular relevance to this project, the mucus barrier on the surface of amphibians. In the research, we will use the Western clawed frog tadpole (species name Xenopus tropicalis) as a tool to address critical gaps in our knowledge concerning the precise details of mucus protection that will be of relevance to animals and humans. The research team have already developed and validated the tadpole as a new and important tool to study mucus biology. Critically, these tadpoles produce gel-forming mucins with structural and functional similarity to gel-forming mucins produced by mammals. Importantly, the specialised mucin producing cells are on the external surface of the tadpole thereby allowing easy access and ready manipulation. This is in stark contrast to the comparable internal mucosal surfaces of mammals which are difficult to access involving extensive tissue damage. Moreover, this simple non-mammalian organism is easy to genetically manipulate and reproduces quickly. This unique combination of features makes the tadpole model ideally suited for the research proposed in this application and will provide valuable insight into evolutionarily conserved mechanisms of mucin and mucus function. In this research project, we will use the tadpole model to define the make-up, formation, organisation and function of mucus produced under normal conditions and how these change after infection with a disease-causing bacterium found in their native environment. Moreover, after genetically changing the gel-forming mucins to alter their nature, we will define specific roles for the different parts of these complex molecules in mucosal protection. Thus, the overall aim of the proposal is to exploit the tadpole model system we have developed to define how mucus changes over-time and how this specifies its protective function. Our program of work will provide a step-change in understanding how mucus performs its protective functions at mucosal sites that will be relevant across the animal kingdom. In particular, providing new insight into how mucus protects against infection.