The major goal of this Program Project is to understand the immunopathology of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the severe complications of dengue virus infections. Dengue is an emerging flavivirus, like West Nile Virus, and is the most common serious arbovirus infection. The morbidity and mortality associated with severe dengue infections is a major public health problem that is increasing in frequency. The frequency of DHF/DSS is much greater during secondary infections with dengue virus strains of a different dengue serotype than that which caused the primary infection. These observations have slowed down vaccine development because of safety concerns. Project #1 consists of three clinical and epidemiology investigations in Thailand. One study is designed to define early immunopathological events during acute dengue infections and will focus on research questions raised during the first years of study. A prospective population-based study of school children is designed to define the roles of dengue cross-reactive T and B cell memory following primary infection on the clinical course of secondary dengue infection, and a study of dengue rashes is planned as a model of dengue pathogenesis. These clinical studies will provide data essential for the later testing of the safety and efficacy of dengue vaccines. Project #2 consists of research to define the host, viral and immunological factors, which induce capillary leakage in DHF .The roles of pre-existing cross-reactive, dengue specific T and B cell memory and of HLA alleles will be analyzed as host and immunological factors. Viral burden, virus-antibody complexes, and NK and T cell responses and immune activation will be assessed during acute infections to define the events leading to DHF. Project #3 will provide analyses of dengue cluster outbreaks as part of the school-based prospective study and determine the effects of vector control on these outbreaks. A Clinical Research Core and an Administrative Core are needed to support these research projects. Our ultimate goal is to develop an improved understanding of the immunopathology of DHF/DSS as a basis for the earlier diagnosis of children at highest risk, and as a foundation for developing logical and safe vaccine approaches to prevent this severe illness.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-YL-M (M1))
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Repik, Patricia M
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University of Massachusetts Medical School Worcester
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Park, Sangshin; Srikiatkhachorn, Anon; Kalayanarooj, Siripen et al. (2018) Use of structural equation models to predict dengue illness phenotype. PLoS Negl Trop Dis 12:e0006799
Salje, Henrik; Cummings, Derek A T; Rodriguez-Barraquer, Isabel et al. (2018) Reconstruction of antibody dynamics and infection histories to evaluate dengue risk. Nature 557:719-723
Kang, Jeon-Young; Aldstadt, Jared (2017) The Influence of Spatial Configuration of Residential Area and Vector Populations on Dengue Incidence Patterns in an Individual-Level Transmission Model. Int J Environ Res Public Health 14:
Srikiatkhachorn, Anon; Mathew, Anuja; Rothman, Alan L (2017) Immune-mediated cytokine storm and its role in severe dengue. Semin Immunopathol 39:563-574
Rattanamahaphoom, Jittraporn; Leaungwutiwong, Pornsawan; Limkittikul, Kriengsak et al. (2017) Activation of dengue virus-specific T cells modulates vascular endothelial growth factor receptor 2 expression. Asian Pac J Allergy Immunol 35:171-178
Kalayanarooj, Siripen; Rothman, Alan L; Srikiatkhachorn, Anon (2017) Case Management of Dengue: Lessons Learned. J Infect Dis 215:S79-S88
Moulton, Steven L; Mulligan, Jane; Srikiatkhachorn, Anon et al. (2016) State-of-the-art monitoring in treatment of dengue shock syndrome: a case series. J Med Case Rep 10:233
Srikiatkhachorn, Anon; Yoon, In-Kyu (2016) Immune correlates for dengue vaccine development. Expert Rev Vaccines 15:455-65
Rothman, Alan L; Ennis, Francis A (2016) Dengue Vaccine: The Need, the Challenges, and Progress. J Infect Dis 214:825-7
Townsley, E; O'Connor, G; Cosgrove, C et al. (2016) Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol 183:419-30

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