Dave Thornton, BSc PhD
Research in my laboratory is focused on understanding how the sticky, gel-like substance mucus protects the body. Mucus coats the insides of our outsides and protects the delicate surfaces of the body (not protected by skin) against attack from a range of external agents (eg. noxious gases, toxic substances, acid, and bugs). Our research is currently focused on two major topics, the first is how mucus protects the lungs (in humans and horses), and the second concentrates on the role of mucus in protection against gut-living parasitic worms.
In the lungs, mucus is essential in keeping the airways free from obstruction. This is achieved in conjunction with hair-like cells (cilia), mucus traps inhaled bugs and particles and the cilia beat and move the mucus up to the throat where it is swallowed. In common diseases like human and horse asthma, cystic fibrosis and chronic bronchitis too much mucus is produced; in addition, the mucus is stickier than normal. This results in mucus that is not adequately removed from the lungs and this has a variety of consequences including airflow obstruction, infection, damage to lung tissue and problems with breathing. We are trying to understand how mucins, the molecules that give mucus its gel-like appearance, contribute to the abnormal properties of mucus in disease.
Infections by gut-living whipworms are a major public health problem, mainly in the developing world. Some people are susceptible to worm infection and develop a long-term infection. However, others are resistant to infection and able to expel the worms before they fully develop. For these studies we are using a mouse model of human whipworm infection. We discovered that mucus of infected resistant mice contained a mucin (called Muc5ac) that is not usually present in the gut, and that Muc5ac can directly impair the health of the worm. Furthermore, in its absence mice were unable to expel any worms and suffered long-term infection. This work has shown that the mucus barrier and its mucin components are an essential part of a well-coordinated response to get rid of gut-living worms. We are actively investigating the details of how Muc5ac performs this important function.
The scientific story
The role of mucins in the protection of mucosal surfaces
The overall aim of my research is to define the roles of polymeric mucins in mucosal biology. At present my main focus is to explore the roles of these glycoproteins in (i) respiratory disease, and (ii) protection against intestinal nematodes. The airways mucus gel performs a critical function in defending the respiratory tract against pathogenic and environmental challenges. However, overproduction of airways mucus with abnormal transport properties is an important pathologic feature of common respiratory disorders. In normal physiology, the polymeric mucins MUC5AC and MUC5B provide the organizing framework of the airways mucus gel and are major contributors to its transport properties. Entanglements, along with specific non-covalent interactions, of these polymers are key elements in mucus gel formation. Importantly, we have shown the relative amounts of MUC5AC and different glycosylated variants of MUC5B are altered in hypersecretory disease compared to normal airways mucus. However, at present there is no definitive link between changes in mucus transport properties and either mucin biochemistry or macromolecular structure. Currently we are investigating the role(s) of MUC5AC and MUC5B, and their equine orthologues, in human asthma and cystic fibrosis, and in equine recurrent airway obstruction.
In the other main focus of my research (in collaboration with Professor Richard Grencis), we are actively exploring the function of mucins and other goblet cell products, in intestinal nematode infection. For these studies we are using the nematode Trichuris muris (T. muris) in a mouse model of human Trichuriasis. Expulsion from the intestine of T. muris is dependent on TH2-associated cytokines. Our studies have highlighted that the mucus barrier is a significant component of the well-coordinated response initiated against the nematode, influenced by the TH2-type cytokines. Work is on going to define the functional role of the mucins in the expulsion of intestinal dwelling nematode parasites.
Tel: +44 (0) 161 275 5647
Recent key publications
Dubaissi, E., Rousseau, K., Lea, R., Soto, X., Nardeosingh, S., Amaya, E., Thornton D.J. and Papalopulu, P. (2014). A secretory cell type develops alongside ionocytes, goblet and multiciliated cells and provides a protective, anti-infective, function in the frog embryonic mucociliary epidermis. Development. 141, 1514-25. PubMed
Hasnain, S.Z., Evans, C.M., Roy, M., Gallagher, A.L., Kindrachuk, K.N., Barron, L., Dickey, B.F., Wilson, M.S., Wynn, T.A., Grencis, R.K. and Thornton, D.J. (2011) Muc5ac: A critical component mediating the rejection of the eneteric nematode, Trichuris muris. J. Exp. Med. 208, 893-900. PubMed
Ridley, C., Kouvatsos, N., Raynal, B.D., Howard, M., Collins, R.F., Desseyn, J-L., Jowitt, T.A., Baldock, C., Davis, C.W., Hardingham, T.E. and Thornton, D.J. (2014). Assembly of respiratory mucin MUC5B: a new model for a gel-forming mucin. J Biol Chem. 289, 16409-120. PubMed