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 #
5R01NS072298-05
Application #
8840328
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wong, May
Project Start
2011-09-01
Project End
2016-09-30
Budget Start
2015-04-01
Budget End
2016-09-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Lainez, Nancy M; Jonak, Carrie R; Nair, Meera G et al. (2018) Diet-Induced Obesity Elicits Macrophage Infiltration and Reduction in Spine Density in the Hypothalami of Male but Not Female Mice. Front Immunol 9:1992
Wohlfert, Elizabeth A; Blader, Ira J; Wilson, Emma H (2017) Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle. Trends Parasitol 33:519-531
Ghosh, Debopam; Wikenheiser, Daniel J; Kennedy, Brian et al. (2016) An Atypical Splenic B Cell Progenitor Population Supports Antibody Production during Plasmodium Infection in Mice. J Immunol 197:1788-800
David, Clément N; Frias, Elma S; Szu, Jenny I et al. (2016) GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii. PLoS Pathog 12:e1005643
Landrith, Tyler A; Harris, Tajie H; Wilson, Emma H (2015) Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain. Semin Immunopathol 37:261-70
David, Clément N; Frias, Elma S; Elix, Catherine C et al. (2015) Antitumor activity of a polypyridyl chelating ligand: in vitro and in vivo inhibition of glioma. ASN Neuro 7:
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
McGovern, Kathryn E; Wilson, Emma H (2013) Role of Chemokines and Trafficking of Immune Cells in Parasitic Infections. Curr Immunol Rev 9:157-168
Ghang, Yoo-Jin; Schramm, Michael P; Zhang, Fan et al. (2013) Selective cavitand-mediated endocytosis of targeted imaging agents into live cells. J Am Chem Soc 135:7090-3
McGovern, Kathryn E; Wilson, Emma H (2013) Dark side illuminated: imaging of Toxoplasma gondii through the decades. Parasit Vectors 6:334

Showing the most recent 10 out of 17 publications