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Alphaviruses and arthritis
Ross River virus and chikungunya virus are mosquito-borne alphaviruses that cause arthritic disease in humans. Ross River virus causes up to 8,000 cases per year in Australia and chikungunya virus has recently re-emerged in the Indian Ocean and India to produce the largest epidemic ever known for this virus (estimated 1.4-6.5 million cases). We have recently established a wild type adult mouse model of chikungunya virus arthritis being widely used for testing interventions. In collaboration with Drs A. Khromykh and R Hall (The University of Queensland), G Pijlman (Wageningen University, Holland), Helder Nakaya and Bali Pulendran (Emory Vaccine Center, Emory, USA) and S. Mahalingam (Griffith University) and we are testing interventions, unravelling the host pathogen relationships and immunopathology of the arthritic disease caused by these viruses. Arthritic disease is driven primarily by a pronounced infiltrate of monocytes/macrophages and proinflammatory cytokine induction, not dissimilar to that seen in rheumatoid arthritis. We are also collaborating with the to test new chikungunya vaccines in our recently established wild type adult mouse model of chikungunya virus arthritis.
SerpinB2 / Plasminogen activator inhibitor type-2
SerpinB2 is a serine protease inhibitor induced in nearly all types of inflammation and is a major product of activated macrophages. SerpinB2 dysregulation and mutation have been associated with pre-eclampsia, asthma, lupus, scleroderma and periodontitis. This serpin is also known as Plasminogen Activator Inhibitor Type-2 (PAI-2) and is traditionally viewed as an inhibitor of the extracellular urokinase plasminogen activator. However, although this activity can be readily demonstrated in vitro, under what circumstances, or even whether, this occurs in vivo has remained elusive. SerpinB2 knockout mice do not show any discernable defects in plasminogen activation. Using these mice we have recently shown that a physiological role of macrophage SerpinB2 is suppression of Th1 immunity. We are currently investigating the molecular mechanisms involved.
Pancreatic cancer and Sin1
Gemcitabine remains the cornerstone of pancreatic cancer treatment. Nevertheless, treatment efficacy remains low with 5% five year survival. A key endeavour to improve PC treatment is the search for drugs that might effectively synergise with gemcitabine. We have recently demonstrated that cells deficient in a gene called Sin1 are highly resistant to gemcitabine treatment. The Sin1 gene makes a number of distinct proteins and our research aims to determine which Sin1 proteins are important in regulating gemcitabine sensitivity and how these Sin1 proteins achieve this activity. Understanding Sin1 activity with respect to gemcitabine treatment may indicate what pancreatic tumours will be resistant to gemcitabine and potentially identify other drugs that may be used together with gemcitabine to improve treatment outcomes.
Contract research and development in the Immunovirology Laboratory
The Immunovirology Laboratory continues to undertake contract research and development for a number of Australian and international pharmaceutical companies. Customers have included LEO Pharma (Denmark), Bavarian Nordic (Denmark), Aventis (France), NewBiomed Pika (Singapore), CSL Ltd., C-Bio Ltd., Virax Holdings Ltd and Peplin Ltd (Australia). We have produced a number of patents, including (i) a series for Peplin Ltd. and LEO Pharma, who have developed a new topical anti-cancer treatment (PEP005/ingenol mebutate/Picato), which recently received FDA approval for treatment of actinic keratoses, and (ii) CBio Ltd. who have developed a new anti-inflammatory drug (Cpn10 / XToll).