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Summary: Dr. Karupiah is studying the roles of leukocyte subsets, cytokines, chemokines, and some signaling molecules in viral infection and disease.

The host response to viral infection consists of an early, innate response that profoundly influences and directs the type of adaptive response that is generated. We have investigated the contribution of neutrophils, one of the earliest leukocyte subsets to respond to infection, in the development of effective adaptive responses for the clearance of virus pathogens. We used the monoclonal antibody (mAb) RB6–8C5, which recognizes Gr-1 (Ly6G) on neutrophils. It also cross-reacts with Ly6C, which is expressed on plasmacytoid dendritic cells (PDC) and on activated CD8⁺ T lymphocytes. We utilized the mousepox model (ectromelia virus infection of mice), a disease that is similar in many ways to smallpox, in C57BL/6 mice to show that Gr-1 cells play a significant role in the resolution of virus infection. In contrast to control animals in which virus is cleared effectively without any observable symptoms, animals depleted of Gr-1⁺ cells are highly susceptible to mousepox, with mortality rates of up to 100 percent. Intriguingly, virus-specific, cytotoxic T lymphocyte (CTL) lytic activity and interferon-gamma (IFN-gamma) production by splenocytes were at least 9- to 27-fold lower in Gr-1⁺ cell–depleted mice compared with control antibody-treated animals. This suggested that Gr-1⁺ cells are critical for the generation of an optimal CTL response and cytokine production. Flow cytometric analysis indicated that activated CD8⁺ T lymphocytes are not depleted by RB6–8C5 treatment. Further, depletion of Gr-1⁺ cells did not affect the generation of CTL response to vaccinia, a poxvirus that is closely related to ectromelia virus. We are currently elucidating the Gr-1⁺ cell–dependent mechanisms that regulate the adaptive arm of the immune response, namely CTL and IFNgamma production, which in turn results in ectromelia virus clearance. The availability of mAb specific for PDC will allow us to dissociate the roles of PDC and neutrophils in the generation of adaptive immunity.