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BIOGRAPHY:
Dr. Schofield received his Ph.D. in microbiology from the Queensland Institute of Medical Research in Brisbane, Australia in 1986. From 1986 until 1988 he conducted postdoctoral research in the Department of Medical and Molecular Parasitology of the New York University School of Medicine in the United States, where he subsequently held the position of Junior Faculty Instructor until 1990. From 1990 until 1994 he was Staff Scientist at the Medical Research Council National Institute for Medical Research in London. He is currently Senior Research Fellow of the Laboratory of Malaria Immunology at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. His HHMI project is entitled "Major Susceptibility and Resistance Loci for Severe Malarial Pathogenesis Within the Murine Natural Killer Complex."
RESEARCH ABSTRACT SUMMARY:
Major Susceptibility and Resistance Loci for Severe Malarial
Pathogenesis Within the Murine Natural Killer Complex
The natural killer complex (NKC) is a large dense cluster of
immunoregulatory loci encoding several receptor families involved in
the control of natural killer (NK) and NKT cell function. In common
with the major histocompatibility complex (MHC), the NKC is highly
polymorphic. Both NKC and MHC polymorphisms are thought to be
maintained by immunity to infection. Interestingly, diverse
interactions are emerging between some of the main products of the MHC
and NKC clusters, especially Class I–like molecules and NK activation
and inhibitory receptors. To date, NKC biology has been elucidated
largely in viral and cancer models. We have made the novel and
intriguing observation that NKC receptors in general and specific
members of the Ly49 family in particular are critical determinants of
fatal Plasmodium berghei murine malarial pathogenesis. In viral
systems, NKC receptors are involved in the control of pathogen
replication. By contrast, in malaria, NKC alleles are major
pathogenicity determinants through mechanisms that are independent of
pathogen replication, that is, through significant regulatory effects
on fatal inflammatory processes. Our data in malaria provide the first
evidence for critical NKC involvement in the response to a nonviral
infectious agent. Unlike viral infections that infect MHC Class
I–positive nucleated host cells, malaria blood stages exclusively
infect MHC Class I–negative erythrocytes, and Class I–restricted immune
responses play no role in the immunological control of blood-stage
infection. Presumably, the “Missing Self” negative
regulation of NK cells through Class I–reactive inhibitory receptors
operates through different mechanisms where red cells are involved.
Elucidating the details of NKC/malaria biology may thus prove highly
informative to our rapidly expanding understanding of innate immune
system biology. Moreover, our findings are doubly important because
murine Plasmodium berghei infection has emerged as a preeminent
model of malarial pathogenesis, with clearly established relevance to
the 2 million annual human pediatric malarial fatalities.
Photo: Kent Kallberg, Kallberg Studios
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