Understanding the mechanisms that control inflammation in the CNS is critical to finding therapies for limiting damage to the brain from pathogens or neurodegenerative disease. Yet our knowledge is primarily limited to the adhesion molecules that facilitate entry to this site and not the factors that influence inflammatory cells once within the brain. Infection with the protozoan parasite Toxoplasma gondii leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency. The absence of an appropriate immune response leads to the development of Toxoplasmic encephalitis (TE) and is therefore a common cause of AIDS related fatalities. Toxoplasma is an extremely common human infection, yet, in the immune- competent host there is no apparent pathology related to continuous inflammation in the brain. Thus, T. gondii infection leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. A hypothesis being examined in our lab is that during chronic infection, cell migration can be guided in the brain by chemokine networks thereby controlling infection and limiting tissue damage. Recent studies of ours have demonstrated that following Toxoplasma infection, the presence of a reticular network is formed on which T cells migrate within the parenchyma of the brain. In addition, the chemokines CCL19 and CCL21 are significantly upregulated with cables of CCL21 associated with migrating T cells. These chemokines, known for their role in T cell and dendritic cell migration in the periphery, have not been well studied in the context of migration within the CNS. Experiments will be conducted to test the hypothesis that increased expression of CCL19/CCL21 in the infected brain is a mechanism to guide leukocytes within the brain parenchyma to control infection. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling the multiple infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to manipulate a pathological or deficient immune response in the CNS.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072298-03
Application #
8450157
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wong, May
Project Start
2011-09-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$320,863
Indirect Cost
$109,769
Name
University of California Riverside
Department
None
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Notarangelo, F M; Wilson, E H; Horning, K J et al. (2014) Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia. Schizophr Res 152:261-7
Noor, Shahani; Wilson, Emma H (2012) Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation. J Neuroinflammation 9:77