Novel research could lead to drug and vaccine treatment of human diseases caused by mosquito-borne viruses.
Professor Suresh Mahalingam is a viral immunologist with a particular interest in the development, treatment and prevention of viral-induced inflammatory diseases. His latest research seeks to understand how viruses, particularly mosquito-transmitted viruses, cause inflammatory disease.
Professor Mahalingam has made numerous advances in viral inflammatory disease over the last 15 years. His focus has been on arthritogenic alphaviruses, which cause debilitating joint pain, and include Ross River virus (RRV), chikungunya virus (CHIKV), Barmah Forest virus (BFV), mayaro virus (MAYV) and o’nyong’nyong virus (ONNV).
‘RRV is the most prevalent mosquito-transmitted virus in Australia and infects thousands of people annually. Climate change is expected to result in increased range and activity of mosquito-borne infectious diseases in Australia,’ said Professor Mahalingam.
Together with Doctor Brett Lidbury, Professor Mahalingam’s team developed a mouse model of RRV. Using the RRV model, Professor Mahalingam and team have identified numerous immune molecules and cells that contribute to the disease, including the important genetic features of the alphaviruses that determine the extent of disease.
‘The model we developed very closely mimics the joint disease in human RRV infection and has proven to be an extremely valuable tool for understanding joint disease resulting from other alphavirus infections such as chikungunya virus,’ explained Professor Mahalingam.
With NHMRC Project Grant funding over a number of years, Professor Mahalingam and team found that arthritogenic alphaviruses can directly infect joint tissues, such as bone, muscle and cartilage, leading to tissue damage and bone loss. This could explain the long-term joint pain that is often associated with these viruses (as well as with other viruses such as dengue virus).
Collaborations with rheumatologists, orthopaedic surgeons and infectious disease physicians have enabled Professor Mahalingam and team to bridge the gap between basic and clinical research and allowed them to translate basic laboratory findings directly to drug development for human diseases.
Professor Mahalingam’s work has cautioned rheumatologists worldwide about prescribing tumour necrosis factor (TNF) inhibitor drugs in areas where arthritogenic viruses are endemic.
‘Combining our research findings in the mouse model with human tissue samples enabled us to discover that the use of TNF inhibitor drugs are strongly contraindicated for viral arthritis. While these drugs are highly effective in rheumatoid arthritis, they are very damaging in animal models of viral arthritis, leading to increased tissue damage and higher viral loads in key target tissues,’ said Professor Mahalingam.
In the last five years, Professor Mahalingam has worked towards applying the knowledge of how alphaviruses cause joint disease to drug development. His strategy has focused on drug “re-purposing”, which involves testing drugs already developed and approved for other conditions.
‘Our strategy avoids the massive costs involved in developing new drugs from scratch and can be achieved in a far shorter timeframe. One success from this approach was the identification of pentosan polysulphate (PPS) as a new drug for treating alphavirus infections’, said Professor Mahalingam. This work was carried out in Professor Mahalingam’s lab by Dr Lara Herrero.
PPS is now in phase 2 clinical trials for the treatment of RRV infection, with a view to undertake further trials next year in Central America for CHIKV infection. The drug has been patented and licensed to Australian biotech firm Paradigm Pharmaceuticals, which is funding the trials.