Toxoplasma gondii is an intracellular protozoan parasite that is the causative agent of Toxoplasmosis. Toxoplasma infection in mice provides an excellent experimental model for understanding food borne infections and infections of the brain. The overall goal of this project to gain a deeper understanding of how the mammalian immune system responds to Toxoplasma infection by tracking parasites and immune cells in vivo. Our experimental approach makes extensive use of 2-photon microscopy to visualize the dynamics of parasite and immune cell interaction in living tissues. In the previous funding period, we have assembled the tools to visualize and quantitate interactions between parasites and T cells and other cells of the immune system, and have begun to address the fundamental question of where, when, and how parasites and immune cells interact in vivo. Our initial studies have provided a framework for further exploration and have led to a number of testable hypotheses about the role of T cell-parasite interactions during infection. In the current application, we propose experiments designed to test these hypotheses, and to continue building a more complete picture of the cellular events during Toxoplasma infection. Specifically we will examine early parasite spread and host immune response after oral infection (Aim 1) and examine the regulation of T cell response during chronic infection in the brain (Aim 2).

Public Health Relevance

Toxoplasma gondii is a parasite that causes birth defects or brain infection in immunocompromised adults. We are using a mouse infection model and advanced microscopy methods to gain a better understanding of how the immune system protects against the parasite and how the parasite attempts to evade the immune system. Because Toxoplasma is a food borne pathogen and can lead to intestinal pathology, these studies have relevance for the development of mucosal vaccines and the treatment and prevention of other food borne pathogens, and the treatment of inflammatory bowel diseases, as well as infections of the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065537-09
Application #
8484781
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Wali, Tonu M
Project Start
2005-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$357,118
Indirect Cost
$124,468
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Han, Seong-Ji; Melichar, Heather J; Coombes, Janine L et al. (2014) Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii. Immunol Cell Biol 92:872-81
Grover, Harshita Satija; Chu, H Hamlet; Kelly, Felice D et al. (2014) Impact of regulated secretion on antiparasitic CD8 T cell responses. Cell Rep 7:1716-28
Coombes, Janine L; Charsar, Brittany A; Han, Seong-Ji et al. (2013) Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread. Proc Natl Acad Sci U S A 110:E1913-22
Ingram, Wendy Marie; Goodrich, Leeanne M; Robey, Ellen A et al. (2013) Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. PLoS One 8:e75246
Melichar, Heather J; Li, Ou; Herzmark, Paul et al. (2011) Quantifying subcellular distribution of fluorescent fusion proteins in cells migrating within tissues. Immunol Cell Biol 89:549-57
Coombes, Janine L; Robey, Ellen A (2010) Dynamic imaging of host-pathogen interactions in vivo. Nat Rev Immunol 10:353-64
Chtanova, Tatyana; Han, Seong-Ji; Schaeffer, Marie et al. (2009) Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node. Immunity 31:342-55
Chtanova, Tatyana; Schaeffer, Marie; Han, Seong-Ji et al. (2008) Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29:487-96