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BIOGRAPHY:
Dr. Karupiah is currently NH and MRC Senior Research Fellow and Leader of the Infection and Immunity Group in the Division of Immunology and Genetics at the John Curtin School of Medical Research, Australian National University, in Canberra, where he also received his PhD in viral immunology. He did postdoctoral research from 1990 to 1994 in the United States at the National Institutes of Health, National Institute on Allergy and Infectious Diseases, first in the Laboratory of Viral Diseases, and later in the Laboratory of Immunopathology. He has received two Fogarty Fellowships and, in 1999, the Medical Foundation Fellowship from the University of Sydney. His research interests are in the broad area of virus-host interactions, and he pursues this goal using a range of viral and animal models. An integral component of his research is the attempt to understand the roles of leukocyte subsets, cytokines, chemokines, and some signaling molecules in viral infection and disease.
RESEARCH ABSTRACT SUMMARY:
The Role of Plasmacytoid Dendritic Cells and Neutrophils in the
Generation of an Antiviral Immune Response
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.
Photo: Kent Kallberg, Kallberg Studios
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