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High throughput proteomics could hold the key to new treatment strategies
20 February 2012
The pathogenesis of dengue virus, which infects millions of people worldwide, has so far eluded scientists whose efforts to understand the disease have yielded limited insights. But after years dedicated to investigating the molecular and cellular biology of dengue fever, virologists at the University of Bristol are using novel approaches to identify cellular proteins that could inform more effective drug design and diagnostic development.
Dengue is the most important insect-borne viral disease of humans, with up to 50 million people infected each year. Infection with one of the four types of dengue virus (DENV) may result in a spectrum of illnesses ranging from dengue fever, a mild flu like illness to the potentially fatal dengue haemorrhagic fever. The number of individuals afflicted with dengue is expected to rise due to the effects of globalisation, including increased travel and urbanisation of human populations and the expanded geographical distribution of its mosquito vector.
Despite intensive research, dengue disease is not wholly understood, and there are no vaccines or anti-viral treatments available that can safely or effectively control the disease.
Currently the leading vaccines under development are live-attenuated vaccines; patients are infected with a modified version of the virus which bolsters their immunity to it without allowing it to cause disease. Severe dengue disease occurs most commonly in sequential infections with different DENV types. A vaccine based on only a single DENV type has the potential to predispose patients to severe illness if they are subsequently infected with a second DENV type. Therefore, it is believed that a successful DENV vaccine must include components from all four DENV types.
Dr Andrew Davidson from the School of Cellular and Molecular Medicine was one of a number of researchers who pioneered techniques to manipulate the DENV genome in the lab. This research has been used to create genetically engineered live attenuated vaccines which are in advanced clinical testing and cell based systems for antiviral screening that are being used by researchers and clinical institutes world-wide.
One of the challenges now being addressed by Dr Davidson’s lab is to understand how DENV interacts with the immune system, by examining the changes that occur to host protein levels in infected cells. Using the high-throughout proteomics facilities in the Faculty of Medical and Veterinary Sciences, Dr Davidson is leading studies that examine changes in cellular protein profiles in response to infection with different DENV types. The research is directed at identifying specific interactions between viral proteins and host proteins that either restrict or are essential for viral replication. The findings of the research could have a number of potential uses for the control of dengue. A drug designed to target and modify interactions between host and viral proteins could prevent the virus from replicating. Engineering of the DENV genome to prevent specific interactions between viral and host proteins could be used for improved vaccine design. In addition, proteins that act as biomarkers for the development of dengue disease may be identified and can be used for diagnostic development.
Although the work is at an early stage it could represent a significant advance: “Identifying proteins that are either critical for viral defence or of use as biomarkers for disease could reveal important therapeutic and diagnostic insights,” says Dr Davidson. “At present, most people initially develop a mild form of the disease. However, there is no way of distinguishing dengue fever from [the more severe] dengue haemorrhagic fever because the response and effects only become apparent at a stage where treatment may be too late.
“Anyone presenting with symptoms is therefore likely to be admitted to hospital, whether or not their infection is life threatening, which creates a huge burden for the health care systems in large parts of the developing world where the virus is most prevalent.”
The next step would be to ultimately apply these findings in the field: “If we could identify a protein that acts as a biomarker for the development of severe disease, in the blood of patients presenting with symptoms of dengue fever, clinicians would know what to look for, they would know what stage of the disease the patient was at, and they could treat patients at a much earlier stage.”
Key facts:
- DENV is primarily found in tropical and subtropical regions, however cases have been reported in Mediterranean countries such southern France.
- The incidence of dengue has increased 30-fold over the last 50 years. Up to 50 million infections are now estimated to occur annually in over 100 endemic countries and as the disease continues to spread, approximately one third of the world’s population is at risk. [World Health Organisation].
- DENV infection generally results in dengue fever, a debilitating but self-limited febrile disease. However, complications may arise, leading to the potentially fatal dengue haemorrhagic fever/dengue shock syndromes (DHF/DSS).
- Research approaches pioneered by Bristol academics have informed worldwide efforts to combat the disease, including work with the Novartis Institute of Tropical Diseases (NITD).
- Bristol’s high-tech proteomic facilities are being used to identify changes in host cell protein profiles during DENV infection. The laboratory research findings will be translated to the clinic to improve DENV antiviral and diagnostic development which is urgently needed to control the spread of dengue.
Please contact Aliya Mughal for further information.
Identifying proteins that are either critical for viral defence or of use as biomarkers for disease could reveal important therapeutic and diagnostic insights.