Academic Background
Education:
- B.A., Queens College, 1983
- M.D., Eastern Virginia Medical School, 1986
Post-Graduate Training:
- Internal Medicine - Washington Hospital Center, 1986-89
- Infectious Diseases - University of Massachusetts Medical Center, 1989-92
Research Interests
- Immunopathogenesis of viral infections
- Human T cell responses to flavivirus infections including dengue and West Nile virus
- Human immune responses to novel viral vaccines
My laboratory studies T lymphocyte responses to viral infections and their role in protection as well as immunopathogenesis of disease. The study of T cell responses to natural viral infections can be utilized towards the development and testing of viral vaccines. Dengue virus, yellow fever virus, West Nile virus and Japanese encephalitis viruses are the current model systems under study.
Dengue viruses
Dengue viruses, of which there are four serotypes, are transmitted from human-to-human by mosquitoes in tropical and subtropical regions of the world. In some individuals, dengue virus infections manifest as dengue hemorrhagic fever (DHF), which is characterized by plasma leakage, and can lead to life-threatening shock. Our laboratory hypothesizes that DHF is an example of immunopathology caused by the ‘over’ responses of memory T cells. The role of other arms of the adaptive immune system in regulating disease severity, such as pre-existing antibodies that mediate neutralization, enhancement and antibody-dependent cell cytotoxicity (ADCC) are also under investigation. As part of an ongoing multi-center international NIH-funded Program Project, I spent over 4 years in Thailand trying to elucidate the role of immune activation in the development of plasma leakage in children with DHF. These field studies are currently ongoing and valuble samples from these children are utilized in our laboratory to address these immune mechanisms in disease pathogenesis.
West Nile virus
West Nile virus (WNV), another mosquito-borne virus which is rapidly emerging in the United States, often produces subclinical infection or an acute viral syndrome, West Nile fever. Ina minority of infected people the infectioncauses neurological illness -l WNV encephalitis. CD8 + T cells can be demonstrated in the brains of individuals who have succumbed to WNV encephalitis.T cells likely play a role in protecting the host from neuroinvasion and once neuroinvasion has occurred, T cells may also play a role in disease pathogenesis. Studies are underway for detailed analysis of memory T cell responses in humans infected by WNV, including CTL responses and interferon gamma production by WNV-specific T cells using IFN-gamma ELISPOT and intracellular cytokine staining assays. In addition, we have established a murine model of WNV encephalitis to study the role of flavivirus cross-reactive T cells in protection from WNV illness as well as their role in disease pathogenesis.
Heterologous immunity to flaviviruses
Flaviviruses co-circulate in many parts of the world. Due to relatively conserved genomic sequences, the effect of pre-existing immunity to one flavivirus on host immune responses to a secondary flavivirus can vary. In the case of dengue viruses, secondary infection may lead to an increase in disease severity. Some human epidemiologic and animal model studies suggest that other combinations of flaviviruses may lead to protection from disease. My laboratory is investigating the role of pre-existent flavivirus cross-reactive T cell and antibody responses on epitope hierarchy, disease outcome and viral burden in murine models, including human HLA transgenic mice.
Novel vaccines
Novel vaccines, such as DNA vaccines and chimeric virus vaccines, may induce antibody and/or T cell memory in immunized individuals. My laboratory is actively involved in evaluating T cell responses to such novel vaccines in the hope of developing much needed first and second generation vaccines for the US and the developing world.