Mucosal surfaces are the outer parts of the body that line the lungs, gut and reproductive systems. The majority of important pathogens that cause disease either infect or enter the body via these mucosal surfaces.
The mucosal immune response that develops against many infectious pathogens influences both our ability to fight off such infections, and the susceptibility to disease development. For example, the severity of inflammation that develops at mucosal sites of infection plays a major role in determining which people will develop serious disease, including cancer. One focus of the group’s research is to understand how the host mucosal immune system regulates inflammation caused by pathogenic bacteria. Such inflammation is central to the development of stomach ulcers, as well as stomach and colorectal cancer.
Another important area of the group’s research is vaccine development. For example, the team is examining new ways for vaccines to be delivered via mucosal surfaces, with the aim of making better, more effective vaccines. The group is researching vaccine development against important pathogens including Helicobacter pylori, which causes stomach cancer, and Neisseria meningitidis, a major cause of meningitis in children.
The Muc1 mucin and Helicobacter pylori pathogenesis
Muc1 is the main cell surface mucin lining the gastric mucosal surface. Mutations in this mucin have been associated with increased risk of gastric cancer in humans. The group’s published mouse studies have shown that Muc1 plays a critical role in regulating both the level of colonisation by H. pylori (a human pathogen and main agent causing stomach cancer) within the gastric mucosa, and the severity of resulting gastritis. The team’s ongoing work is dissecting the mechanism by which Muc1 regulates H. pylori driven gastritis.
Protease Activated Receptors and bacterial-driven inflammation of the gastrointestinal tract
Protease Activated Receptors (PAR) are a family of sensors that detect the presence of proteases released during infection and inflammation. Increasing evidence suggests members of this family play an important part in the regulation of the inflammatory and immune response to infection. For example, the team has shown that PAR1 is an important regulator of H. pylori induced gastritis in mice and that mutations in PAR1 are associated with increased risk of gastric cancer in humans.
The group’s current studies have now demonstrated a potentially important role for PAR1 in regulating bacterial-driven colitis in both mouse models of infection and in childhood inflammatory bowel disease (IBD). Ongoing studies are exploring the specific role of PAR1 in this disease and the mechanism by which PAR1 regulates inflammation in the gastrointestinal tract.
The role of Protease Activated Receptor 2 in infection and inflammation in cystic fibrosis
Cystic fibrosis is a genetically inherited condition, where individuals are particularly prone to respiratory failure due to lung infections. In collaboration with Associate Professor Sarath Ranganathan and the Department of Respiratory Medicine, the researchers are investigating the role of a second member of the PAR family, PAR2, in cystic fibrosis. Preliminary evidence indicates a link between cystic fibrosis pathogenesis and the production of a PAR2-activating protease. The team is currently examining the potential role that PAR2 plays in the inflammation that develops in response to bacterial infections in cystic fibrosis patients.
Developing an immunotherapeutic to protect against stomach cancer
Gastritis caused by Helicobacter pylori infection is the main cause of stomach cancer. The group has identified a bacterial antigen that, when used in a vaccine, induces an immune response that protects against the development of H. pylori-induced gastritis. The researchers are currently exploring the potential use of this vaccine to protect against the development of stomach cancer.
- ImmunoBiology Ltd, Cambridge, UK
- CSL Limited, Melbourne
- Prof Mike McGuckin, Mater Research Institute
- Prof Tim Florin, Mater Research Institute
- Associate Professor Richard Ferrero, Monash Institute of Medical Research
- Professor Hazel Mitchell, University of New South Wales
- Professor Steffen Backert, University of Erlangen, Germany
- Overexpression of IL-11 promotes premalignant gastric epithelial hyperplasia in isolation from germline gp130-JAK-STAT driver mutations. 2019
- NOD1 is required for Helicobacter pylori induction of IL-33 responses in gastric epithelial cells. 2018
- Status of vaccine research and development for Helicobacter pylori. 2018
- Superoxide dismutase from Helicobacter pylori suppresses the production of pro-inflammatory cytokines during in vivo infection. 2018
- Lack of small colony variants of Staphylococcus aureus from lower respiratory tract specimens. 2017
- MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target. 2017
- Mucin 1 protects against severe Streptococcus pneumoniae infection. 2017
- No evidence of a role for mitochondrial complex I in Helicobacter pylori pathogenesis. 2017
- Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity. 2017
- Reduced PU.1 expression underlies aberrant neutrophil maturation and function in β-thalassemia mice and patients. 2017
- Activation of TRIF-dependent and independent immune responses by neisserial heat shock protein complex vaccines. 2016
- Heat shock protein complex vaccines induce antibodies against Neisseria meningitidis via a MyD88-independent mechanism. 2016
- How host regulation of Helicobacter pylori-induced gastritis protects against peptic ulcer disease and gastric cancer. 2016
- Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression. 2016
- The MUC1 mucin specifically inhibits activation of the NLRP3 inflammasome. 2016
- ISCOMATRIX™ adjuvant reduces mucosal tolerance for effective pulmonary vaccination against influenza. 2015
- Protease-activated receptor 1 suppresses Helicobacter pylori gastritis via the inhibition of macrophage cytokine secretion and interferon regulatory factor 5. 2015
- Heat shock protein complex vaccination induces protection against Helicobacter pylori without exogenous adjuvant. 2014
- MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli. 2013
- Vaccine-mediated protection against Helicobacter Pylori is not associated with increased salivary cytokine or mucin expression 2013
- Why can't we make an effective vaccine against Helicobacter pylori? 2013
- Do Helicobacter pylori therapeutic vaccines need to be tailored to the age of the recipient? 2012
- Helicobacter pylori thiolperoxidase as a protective antigen in single- and multi-component vaccines. 2012
- PAR-1 Polymorphisms and Risk of Helicobacter pylori-related Gastric Cancer in a Chinese Population 2012