Our laboratory studies inflammation generated by the innate immune system. This can happen in many different contexts, including during infection, when cells die, or when genetic mutations activate innate immune pathways causing autoinflammatory disease. Inflammation contributes to the development of many chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, amyotrophic lateral sclerosis (ALS) and type 2 diabetes.
Previously we have made discoveries relevant to all of these areas. We maintain close links to industry and the clinic to make sure our discoveries can continue to have a direct effect on human health in the future.
The Masters laboratory has helped discover pathways that drive autoinflammatory disease. For example, we found that an immune sensor called PKR is activated due to proteasome deficiency, and we found that the cytokine G-CSF contributes to inflammatory pathology in the condition APLAID.
We continue trying to find the genetic causes of autoinflammation through the Australian Autoinflammatory Disease Registry (AADRY.org).
Genes of the innate immune system are activated by mutations in a number of hereditary periodic fever syndromes (autoinflammatory diseases). However in many cases the precise immune sensor that is triggered is not immediately clear.
We are particularly interested in innate immune sensors that drive autoinflammatory diseases associated with type I IFN (interferonopathies). These are frequently associated with the buildup of cytoplasmic DNA or RNA, triggering sensors such as cGAS and RigI/MDA5. We are now searching to see if these sensors are responsible for disease in particular inferferonopathies, and where they are not involved we are looking to identify novel sensors.
Project resource: Masters, S. (2019, February 3), Cytoplasmic innate immune sensors, The Biomedical & Life Sciences Collection, Henry Stewart Talks
Team member: Dr Sophia Davidson
Rapid advances in genetics are providing unprecedented insight into functions of the innate immune system, with identification of the mutations that cause monogenic autoinflammatory diseases. However, many patients do not have a mutation in one of the known disease causing genes, or have a novel mutation of unknown pathogenicity.
Therefore we have established an Australian Autoinflammatory Disease Registry (AADRY) with three main goals:
The organising committee for this registry includes clinicians from each of the major centres in Australia that treat patients with autoinflammatory disease. These organisations can enter details of their patients with autoinflammatory disease into an online database managed by the Masters laboratory at WEHI.
Clinicians will be able to search de-identified data to find resources, and network with others who have experience in the treatment of these rare conditions. Based on this registry, individuals and several families who tested negative for a mutation in known autoinflammatory disease genes have now been consented for exome sequencing, blood collected, DNA prepared and exomes sequenced.
Project resource: Cause of rare immune disease identified
Team member: Kelsey Breslin
Innate immune receptors can recognize foreign pathogens and alert the host to infection. More recently it has emerged that these same receptors can also recognise host molecules that are exposed as a result of cell stress or injury, as a surrogate marker of infection. However these same danger associated molecular patterns (DAMPs) can be present as a trigger for diseases such as allergy, autoimmunity and chronic inflammatory disease.
This project will uncover the roles of key innate immune receptors in laboratory models of these diseases, such as inflammatory bowel disease, type 2 diabetes and amyotrophic lateral sclerosis.
Team member: Shouya Feng
We collaborate with many external research groups, including:
Luke O’Neill, Trinity College Dublin; Daniel Kastner, Ivona Aksentijevich and Raphaela Goldbach-Masnky, National Institutes of Health; Eicke Latz and Matthias Geyer, University of Bonn; Dr Bruno Reversade and Franklin Zhoug, Singapore; Andrew Murphy, Baker IDI; Mike Rogers, Garvan Institute; Richard Ferrero, Monash University; Kate Schroder and Kate Stacey, University of Queensland.