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Expansion of QIMR leaves room for more research – parasite, vector, virus research to benefit

Originally published in International Innovation. Download the article -International Innovation

The global impact of chikungunya virus and related alphaviruses is substantial, but a team from the Queensland Institute of Medical Research is developing models and gaining insights into how better to manage the chronic rheumatic diseases caused by these viruses.

With as many as 1.4-6.5 million cases worldwide in a recent outbreak, and a footprint which stretched across tropical Africa and Asia, chikungunya virus (CHIKV) has reemerged as a global problem. Causing a few days of fever followed by weeks to months of chronic rheumatic pain, the disease can be debilitating and occasionally lethal.

A group at Australia’s Queensland Institute of Medical Research (QIMR) has been working on improving our understanding of the arthritic disease. Their use of models has provided unprecedented results, making clear that this is an inflammatory disease driven by virus persisting in macrophages, with disease likely caused by innate and cognate immune responses directed at persistent virus or viral products. These findings have also revealed how important monocytes/macrophages and T cells, as well as their products, are to disease pathogenesis. Earlier in vitro work, together
with recent clinical, histological and molecular analyses in recently established wild-type animal models have provided compelling physiological relevant insights into how these viruses cause disease.

The researchers’ development of a simple wildtype adult mouse model of CHIKV disease has led to numerous collaborative and commercial investigations into new treatments and therapeutic approaches for CHIKV disease. A number of vaccine approaches including simple inactivated whole-virus vaccines, recombinant adenovirus vaccines, nanopatch delivered inactivated whole-virus vaccines and baculovirus vaccines, have all been shown to be highly effective.

However, Professor Andreas Suhrbier who leads the team, argues that CHIKV vaccines may be difficult to develop commercially and deploy effectively given the disease is so unpredictable in its behaviour, reappearing every two to 50 years to produce large epidemics in different parts of the world. Consequently, they are also investing effort in the testing of new biologicals, including neutralising antibodies, and in identifying anti-infl ammatory drugs that could provide more effective treatment.

Building on success

The work has been assisted by new investment in the QIMR, providing new state-of-the-art facilities in a recently completed 15 floor building. Suhrbier is excited about working in this new  environment: “The new building is up and we have moved in, and the biosafety level 3 (BSL3) suites are operational and we now have integrated, fully equipped BSL3 laboratory, animal house and insectory facilities.”

With 20 new research laboratories housing 400 additional scientists, the new building will raise the number of scientists working at the QIMR to over 1,000, thus offering at QIMR a dynamic, high-quality, mutifaceted research environment. With the new building, QIMR is looking to increase the Institute’s research capacity in (inter alia) tropical diseases and immunological interventions. The group’s association with the Australian Infectious Disease Research Centre, the Queensland Tropical Health Alliance and the team’s various national  and international collaborators, together with the new building and particularly the BSL3 facilities, means substantial new scope and capacity has been generated for new academic and commercial collaborations. The team has a substantial track record in generating intellectual property – 17 patents so far – and in undertaking industry-funded collaborative research with large and small, local and international biotech and pharma companies. The Brisbane group will also continue working in the associated areas of inflammation biology and anti-inflammatory drug development and will utilise the ever-expanding resources at QIMR, which include a large number of knock-out and reporter mice allowing the importance of individual infl ammatory and antiviral pathways to be analysed in vivo.

New connections

Suhrbier’s recent collaborative research with Dr Helder Nakaya and Dr Bali Pulendran and their systems biology group at the Emory Vaccine Center in the US, has investigated the similarities
between CHIKV arthritis and rheumatoid arthritis using microarray technology and bioinformatics analyses. The two conditions, an infectious self-limiting viral arthritis and a progressive
autoimmune arthritis, appear to share a significant number of infl ammatory pathways.

“We were really surprised to see the high levels of overlap between these diseases, which have quite distinct aetiologies, and are extremely pleased with the insights provided,” Suhrbier comments.
The work was recently published in the American College of Rheumatology’s monthly journal Arthritis and Rheumatism. These results highlight the potential for using new drugs being developed
for rheumatoid arthritis, also fi nding utility in the treatment of alphaviral arthritides. In broader terms, the project also adds to the growing body of literature that is promoting the notion that the
best way in the future to treat disease is not only to defi ne the disease clinically, but also to define the deregulated molecular pathways involved.

Drugs that target a particular pathway can then be used in the treatment of multiple diseases where that pathway is known to be dysregulated, rather than restricting the use of that drug to a
defi ned clinical presentation.

Knock-out mice

The researchers have been able to exploit the large number of knock-out mice available at QIMR and from collaborators. These mice, deficient in specific immune factors, have dramatically increased our understanding of the importance of specific anti-viral and inflammatory pathways in protection and disease. “What has surprised me is how often a specifi c pathway is largely irrelevant
or extremely critical, and how removal of certain pathways can completely change disease pathology,” notes Suhrbier.

For example, in the Journal of Virology, published by the American Society of Microbiology, the team, together with several international collaborators, published fi ndings that show Interferon Response Factor 7 and 3 (two transcription factors involved in generating the anti-viral interferon α/β responses), were critical for survival after infection.

Surprisingly, Interferon Response Factor 7 and 3 deficient mice died of haemorrhagic fever and shock, an entirely unexpected pathology with broader implications for the regulation of cytokine storms such as those seen during dengue haemorrhagic fever and dengue shock syndrome. “We have recently also shown that depleting TNF or CCR2, two major targets of next generation anti-infl ammatory drugs, can have major detrimental effects on alphaviral rheumatic disease. Such work in knock-out mice can therefore also reveal the potential dangers associated with targeting of specific pathways with new drugs or biologicals,” adds Suhrbier.


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