Dengue virus infections are a serious cause of morbidity and mortality in many areas of the world. The pathogenesis of severe complications of dengue virus infection, dengue hemorrhagic fever (DHF) is important to elucidate for prevention and treatment of DHF. Epidemiological studies have shown that DHF is much more commonly observed during secondary infections with a different serotype of dengue virus from that which caused the primary infection, and it is assumed that DHF is caused by immunopathological mechanisms. We hypothesize that enhanced infection of monocytes by dengue virus-antibody complexes results in marked activation of dengue virus-specific CD4+ and CD8+ T cells and the production of high levels of cytokines which lead to DHF. The goal of this project is to define immunopathological mechanisms which induce DHF, using molecular immunological techniques. No animal models are available to study DHF; therefore, research using human subjects is required. We will elucidate immunopathological mechanisms by analyzing peripheral blood mononuclear cells (PBMC) and plasma of patients with DHF or with uncomplicated dengue fever (D) during the acute phase and after recovery. We will; 1) determine the levels of lymphokine mRNA in CD4+ and CD8+ T cells activated in vivo, 2) determine whether dengue virus-specific CD4=T cells in patients with DHF are Th1 or Th2 by establishing CD4+T cell clones, 3) determine whether dengue virus-specific CD8=T cell clones also produce a characteristic set of lymphokines, and 4) analyze T cell receptor Valpha and Vbeta gene usage and determine whether T cell activation is oligoclonal in vivo. Monocytes are the most permissive human cells for dengue virus replication. We will determine the levels of cytokine mRNA in monocytes from patients with DHF or D. Furthermore, we will determine the levels of infectious dengue virus-antibody complexes in the plasma of patients with DHF. The comparative ability of virus isolates from D and DHF patients to replicate in human monocytes will be tested in tested in this project. If significant differences in growth are detected, we will use this as a biologic marker for selecting typical strains for genome sequencing in project 3. We will define the immunological responses in vivo which result in DHF, based on these analyses of samples from patients with DHF or D. These analyses will provide basic immunological data concerning antibody and T cell responses to dengue virus that are needed for the development of safe and effective dengue vaccines.
| 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 |
| 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 |
| 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: |
| 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 |
Showing the most recent 10 out of 119 publications
