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Dengue Hemorrhagic Fever Network |
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| 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. |
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| 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 |
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| 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. |
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| 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. |
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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
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| 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. |
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| 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. |
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| 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. |
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| Selected Publications |
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Juthathip Mongkolsapaya et
al. Original antigenic sin and apoptosis
in the pathogenesis of dengue hemorrhagic
fever. Nature Medicine 2003;9(7):921-7. |
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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. |
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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. |
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Anavaj Sakuntabhai et al.
A variant in the CD209 promoter is associated
with severity of dengue disease. Nature
Genetics 2005;37(5):507-13. |
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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. |
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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. |
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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] |
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| For further information, contact:
sipml@mahidol.ac.th |
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