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Dengue Hemorrhagic Fever Network
 
Network of Dengue Hemorrhagic Fever and Dengue Virus Research
Overview
      Dengue hemorrhagic fever DHF is one of the major public health problems causing mortality
and morbidity in children of school age in Thailand and the whole of Southeast Asia. The disease, once endemic in the region, has no trend of decreasing but instead is spreading globally, including the American continent. About 100,000 patients were seen in Thailand each year. Four serotypes of dengue viruses, as carried by mosquito Aedes aegypti vector, co-circulate in endemic areas. Epidemiological studies have indicated that most of the DHF occurs in hosts who respond secondarily to different heterotypic virus; suggesting that host immune response plays important roles in the pathogenesis processes. This fact complicates the design and development of dengue vaccines which are badly needed.
     
Formation of Network
     Realizing the magnitude of the problem and the opportunity to provide clinical and public health services to patients, a network of clinicians and scientists was formed, to undertake clinical and basic research projects on DHF, with the aim at unraveling the immuno-pathogenesis of DHF and translating them for practical uses. The network consists of two major groups of laboratories and two clinical sites in Thailand, collaborating with international institutions and colleagues, who share the same interests and to allow our Thai teams to share the state-of-the-art facilities, grant support and intellectual property rights. The two laboratory groups are: the Medical Molecular Biology Unit of the Office for Research & Development, at Siriraj Hospital, Faculty of Medicine, Mahidol University, led by Dr. Prida Malasit; and the Microbiology Department of the Faculty of Medicine (Dr. Nopporn Sittisombut) and the Department of Clinical Immunology of the Faculty of Associated Medical Sciences (Dr. Watchara Kasinrerk), Chiang Mai University. Both institutions operate under their respective universities and as the Medical
Biotechnology Unit/network of the National Center for Genetic Engineering and Biotechnology (BIOTEC) of the National Science and Technology Development Agency (NSTDA). The two clinical sites are Khon Kaen and Songkla Hospitals; and the international sites comprise of: the Weatherall Institute of Molecular Medicine, Oxford University; Department of Immunology, Division of Medicine, Hammersmith Hospital, Imperial College, London; Institute Pasteur and the Centre Nationale Genotypage, Paris; and the Institute of Medical Microbiology and Hygiene, Johannes Gutenberg University, Germany.
 
Activities and Outcome
      With the grants from various sources both in Thailand (Thailand Research Fund, BIOTEC, Faculty of Medicine, Siriraj hospital, Medical Scholar Program, Mahidol University, and private funding from Siriraj Foundation) and abroad (the Wellcome Trust, Medical Research Council, U.K., Pasteur Institute and the Deutsche Forschungsgemeinschaft, Germany), the network managed to conduct two large group of activities. The first group of activities and outputs was to establish infrastructure for of carrying out research on the molecular physiology of dengue and other flaviviruses, including basic molecular immunology/biochemistry, proteomics, quantitation and propagation of viruses, functional tests for viruses, cell culture, dengue serology, virology and generation of monoclonal antibodies
against viral proteins. The network has trained many graduate students and also new staff who later joined the network as lecturers and researchers.
 
 The second activity was a set of research projects, including studies of T cell immune responses; the role of dengue non-structural protein NS1 in the DHF/DSS/DF pathogenesis, the identification of genes associated with clinical phenotypes and production of vaccine candidates using the infectious cDNA dengue clone, and the utilization of infectious cDNA dengue serotype 2 to produce virus mutants, for research and dengue vaccine candidates.

The network published high quality publications, two in the Nature group, and other high impact journals with high citation rates. The series of studies on T cells using the material from the clinical sites, have provided a additional mechanism for the pathogenesis of shock and leakage in DHF/DSS: namely, that there are excessive immune T cell death and
extensive cell-mediated-immune response directed toward the infecting virus, as primed by the "original antigenic sin" from previous infection. The finding is critical since it offers a means of defining the type of responses which lead to inflammation, which should be avoided by any new dengue vaccine to be deployed in the future.
 
The series of studies on dengue non-structural NS1 protein have defined the roles of NS1 in the pathogenesis of DHF/DSS: that the protein which is expressed on the surfaces of dengue infected cells or secreted in external milieu, such as patients’ sera, is capable of activating the complement system. A hypothesis was presented on the roles of the NS1 in inducing vascular leakage, and the potential applications of the work for developing the first diagnostic test for DHF/DSS are being explored.
 
Our database and specimens have led to the identification of genotypes that are associated with dengue fever DF, a milder but patho-physiologically distinct form. The team has also demonstrated the molecular mechanisms as conveyed by the genes. And lastly, the availability of the infectious cDNA dengue serotype 2 clones, has allowed the network to use these models to study the structural/genetic and functional relationships in detail and use the information to form a set of strategies for producing mutant viruses with properties suitable for being tested as candidate dengue vaccines of all the serotypes.
 
Selected Publications
 
Juthathip Mongkolsapaya et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nature Medicine 2003;9(7):921-7.
   
Juthathip Mongkolsapaya et al. T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal? Journal of Immunology 2006;176(6):3821-9.
   
Panisadee Avirutnan et al. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. Journal Infectious Diseases 2006;193(8):1078-88.
   
Anavaj Sakuntabhai et al. A variant in the CD209 promoter is associated with severity of dengue disease. Nature Genetics 2005;37(5):507-13.
 
Sriburi R, Keelapang P, Duangchinda T, Pruksakorn S, Maneekarn N, Malasit P, Sittisombut N. Construction of infectious dengue 2 virus cDNA clones using high copy number plasmid. J Virol Methods 2001;92(1):71-82.
 
Keelapang P, Sriburi R, Supasa S, Panyadee N, Songjaeng A, Jairungsri A, Puttikhunt C, Kasinrerk W, Malasit P, Sittisombut N. Alterations of pr-M cleavage and virus export in pr-M junction chimeric dengue viruses. Journal Virology 2004;78(5):2367-81.
 
Noisakran S, Dechtawewat T, Rinkaewkan P, Puttikhunt C, Kanjanahaluethai A, Kasinrerk W, Sittisombut N, Malasit P. Characterization of dengue virus NS1 stably expressed in 293T cell lines. J Virol Methods. 2007 Feb 27; [Epub ahead of print]
 
For further information, contact: sipml@mahidol.ac.th
 

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