The Role of SPARC during Toxoplasma infection in the Brain

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DESCRIPTION (provided by applicant): Historically the brain was considered an immune-privileged site with little immune- surveillance. We now understand that there is continuous surveillance but that inflammatory responses need to be tightly controlled. Although the mechanisms of this control have been extensively researched the focus has been primarily on the entry of cells and less about the control of inflammation once present in the brain. Toxoplasma gondii is one of the most common human infections in the world with prevalence rates in the USA at 10-30% and with 80% of people infected in parts of Europe and South America. This protozoan parasite leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency as demonstrated in immune-compromised individuals who succumb to Toxoplasmic encephalitis. Yet there is no apparent pathology related to this continuous presence of inflammation in the brain. Thus, T. gondii leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. This enables investigations into the mechanisms that achieve a well-balanced immune response in the CNS. This proposal investigates the control of T cell migration within the brain during infection. Recent studies of ours have demonstrated that following infection; the presence of a reticular network is formed on which T cells migrate. To elucidate the mechanism involved in this migration experiments will be conducted looking at a secreted glycoprotein called "secreted protein acidic and rich in cysteine" (SPARC). This molecule has been associated with developmental processes in the CNS, extracellular matrix deposition and increased cell migration in the periphery, however has not previously been demonstrated during inflammatory responses in the brain. Following Toxoplasma infection there is a significant increase in SPARC in the CNS associated with parasites and inflammation. This proposal tests the hypothesis that SPARC is necessary and facilitates leukocyte migration in the brain during the immune response to Toxoplasma. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to counter the inflammation that is prevalent and causative in many neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: This proposal investigates the regulation of the inflammatory response in the brain during Toxoplasma infection. This is one of the most common human pathogens however, in the absence of an appropriate immune response can lead to fatal encephalitis. Understanding immune regulation in the brain during Toxoplasma infection, in addition to controlling infection in the brain, may provide novel mechanisms to counter inflammation that is prevalent during neurodegenerative diseases.