Research Assistant Professor, Infectious Diseases and Microbiology
2130 Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261
Primary Phone: 967-838-4257
Dynamics of CTL responses to RNA viruses.
Cross-immunity to viral infections (West Nile Virus and dengue Virus).
High throughput analysis of adaptive cell mediated responses to viruses.
Modulation of lymphoid endothelial cell function by flaviviruses (dengue virus).
The primary focus of the lab is the study of the T cell mediated, adaptive immune response to emerging infectious diseases, in particular flaviviruses, such as West Nile virus (WNV) and dengue virus (DENV).
Cytotoxic T lymphocytes (CTL) recognize small protein sequences (peptides) derived from the virus infectious cycle (viral epitopes) and respond by killing infected cell targets as well as by producing a host of immunomodulatory molecules. Together with antibodies they are part of the adaptive immune response and are responsible for clearing the body of infected cells.
It is becoming increasingly clear that, even for viruses that encode small proteomes of only a few thousand aminoacids, several CTL epitopes are recognized in any infected individual. To be able to precisely map the CTL epitope landscape that is primed during acute viral infection and then becomes eventually established in the memory pool is therefore critical to improve our understanding of what are the mechanisms of disease protection and pathogenesis and will eventually lead to the development of successful vaccines.
This epitope landscape is complex because not all the CTL recognize viral peptides equally. These are organized in a ranking relationship among dominant and sub-dominant CTL epitopes called “immune hierarchy”. In the specific case of DENV, which exists in four different serology variants that may co-circulate in the same geographic area, there is the possibility that an upset of the CTL immune hierarchy during infection with serologically different strains leads to increased chance of protection from severe disease.
The ultimate goal of our efforts is to monitor the dynamics of the CTL epitope landscape in longitudinal blood samples from acutely infected individuals. Unfortunately these are extremely precious, often from infants or very young subjects: therefore our laboratory is interested in developing robust high-throughput micro-assays that allow for the testing of several hundred epitope peptide candidates starting from minute amounts of cells.
Another aspect that has the potential to alter the memory pool of virus specific CTL is cross-infection with related viruses that are present in the same locality. Preliminary data from our lab show that subjects that were infected with WNV can respond to a high degree to non-structural proteins (NS3 and NS5) from DENV.
Finally, we have just initiated a collaboration with the newly started Pittsburgh Center for Lymphatic Immunobiology. Here we are looking into the infection of lymphoid tissue derived endothelial cells with DENV and resulting immunomodulatory outcomes.
Previously, we have worked on the role of dendritic cells in viral infections, e.g. HIV-1 and HHV-8.
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