Mucins in Infection and Cancer
Members: Ala Alwan (Research engineer), Debashish Banerjee (Post doc), Emma Skoog (PhD student), Nazanin Nawabi (PhD student) and Pushpa Premaratne (Post doc).
The mucosal tissues of the gastrointestinal, respiratory, reproductive and urinary tracts and the surface of the eye present an enormous surface area to the exterior environment. Mucosal tissues represent t
he site of infection or a route of access for the majority of bacteria that cause human diseases. To protect the epithelial cells, the mucosal surfaces are covered by a layer of secreted mucins that have a decoy/cleaning function, and underneath the mucus layer the cell-surface mucins are a dominant feature of the apical surface of mucosal epithelial cells. The cell surface mucins provide a barrier and signalling function and are involved in tumour metastasis as well as regulation of cell proliferation. In infection, precancerous lesions and cancer, the expression and spatial distribution of mucins change. Each mucin carries around 100 different oligosaccharide structures, and some of these change rapidly in response to infection in a way that alters the bacterial adhesion targets. Thus, the mucin barrier is dynamic and responsive and is likely to play a major role during infection and malignant transformation.
We investigate the role of mucins during host defense against bacteria, as well as the biological function of changes in mucosal mucin expression and glycosylation associated with disease. Currently it is not known whether these changes are beneficial for the host or the pathogen, or if they take part in malignant processes or merely accompany them, and furthering the knowledge in this area may lead to novel ways of treating disease.
The main host-pathogen systems being investigated are: Helicobacter pylori infection and gastric cancer development. H. pylori chronically infects half of the World’s population and is the main aetiological agent causing duodenal ulcers, gastric ulcers, gastric adenocarcinoma and mucosal associated lymphoid tissue (MALT) lymphoma. Gastric cancer is globally the second most prevalent cause of death due to malignancy.
Campylobacter jejuni, enteropathogenic Escherichia coli and enterohaemorrhagic E. coli infection of the intestine. These pathogens are considered to be the major cause of diarrhoeal disease in both the developed and developing world. In the US C. jejuni infection costs up to US $6.2 billion annually, while in the developing world most of the 2-3 million childhood-deaths from diarrhoeal disease which occur each year are caused by these bacteria. Like H. pylori, C. jejuni infection can have long term sequelae including intestinal MALT lymphoma and the debilitating autoimmune disease Guillain-Barre Syndrome.
Important publications:1. Lindén S, Every A, Sutton P, Miles K, Florin THJ, Dubois A, and McGuckin MA, MUC1 limits H. pylori infection by acting as a releasable decoy, PLoS Pathog, October 2009.
2. Lindén S, Mahdavi J, Semino-Mora C, Olsen C, Carlstedt I, Borén T and Dubois A. Role of ABO Secretor Status in Mucosal Innate Immunity and H. pylori Infection. PLoS pathogens, Jan 2008.
3. Lindén S, Dreissen K and McGuckin M. Improved in vitro model systems for gastrointestinal infection by choice of cell line, pH, microaerobic conditions and optimization of culture conditions. Helicobacter 2007, 12(4):341-53.
4. Lindén S, Wickström C, Lindell G, Gilshenan K and Carlstedt I. Four modes of adhesion are used during Helicobacter pylori binding to human mucins in the oral and gastric niches. Helicobacter, April 2008.
5. McAuley J, Linden SK, Png CW, King R, Pennington H, Gendler S, Florin T, Hill G, Korolik V, and McGuckin M.. The Muc1 Cell Surface Mucin is a Critical Element of the Mucosal Barrier to Infection. Journal of Clinical Investigation 2007, 1;117(8):2313-2324
6. McGuckin M, Every A, Skene C, Linden S, Chionh Y, Swierczak A, McAuley J, Harbour S, Kaparakis M, Ferrero R, Sutton P. Muc1 mucin limits both Helicobacter pylori colonization of the murine gastric mucosa and associated gastritis. Gastroenterology 2007 133, 1210-1218
7. Lindén S, Mahadavi J, Hedenbro J, Borén T, and Carlstedt I. Effects of pH on Helicobacter pylori binding to human gastric mucins – identification of binding to non-MUC5AC mucins. Biochemical Journal 2004: 384:263-70.
8. Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikstrom S, Sjostrom R, Linden S, Backstrom A, Lundberg C, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatino B, Gilman RH, Gerhard M, Alarcon T, Lopez-Brea M, Nakazawa T, Fox JG, Correa P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE and Boren T. Functional Adaptation of BabA, the H. pylori ABO Blood Group Antigen Binding Adhesin. Science 2004 Jul 23;305(5683):519-522
9. Lindén S, Nordman H, Hedenbro J, Hurtig M, Boren T, and Carlstedt I. Strain- and blood-group dependent binding of Helicobacter pylori to human gastric MUC5AC glycoforms. Gastroenterology 2002;123:1923-193.