Apicomplexan parasites are responsible for a number of human diseases, including toxoplasmosis, cryptosporidiosis, and malaria, and efforts to develop vaccines and therapeutics against these invaders are hampered by our lack of understanding of how T cell responses to parasites are generated and maintained. In the past funding period of this grant, we have characterized a remarkably potent, naturally occurring CD8 T cell response directed against a parasite protein Gra6, and have shown that T cells with this specificity are expanded rapidly and maintained as a potent effector/memory population long after establishment of a latent infection. In the current application, we will test the hypothesis that the spatial and temporal pattern of presentation of parasite antigens to CD8 T cells is key to generating a potent and sustained effector T cell response, and to allowing effector T cells to deliver effector molecules where they can provide maximum protection with minimal collateral damage.
In Aim 1 we will probe the mechanisms that account for the rapid priming and robust maintenance of this response (Aim 1a), will examine the impact of regulated secretion of the antigen in determining the efficacy of the resulting CD8 T cell response (Aim 1b), and will explore the division of labor between distinct subsets of Gra6 specific T cells (Aim 1c).
In Aim 2 we will examine the relationship between T cell protection and the ability to deliver effector molecules directly to invaded host cells while avoiding damage to non-invaded host cells. The successful completion of these aims will expand our ability to recognize and generate effective CD8 T cell responses, and thus will improve our ability to develop effective treatments against intracellular parasites.

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. The Toxoplasma-mouse infection model is also relevant for how the mammalian immune system protects against the related intracellular protozoan parasites, Plasmodium and Cryptosporidium. Thus, these studies have relevance for the development of therapeutic strategies against a variety of dangerous pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065537-13
Application #
9416053
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wali, Tonu M
Project Start
2005-07-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
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
Chu, H Hamlet; Chan, Shiao-Wei; Gosling, John Paul et al. (2016) Continuous Effector CD8(+) T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population. Immunity 45:159-71
Ueno, Norikiyo; Lodoen, Melissa B; Hickey, Graeme L et al. (2015) Toxoplasma gondii-infected natural killer cells display a hypermotility phenotype in vivo. Immunol Cell Biol 93:508-13
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 7:1716-1728
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
Feliu, Virginie; Vasseur, Virginie; Grover, Harshita S et al. (2013) Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite. PLoS Pathog 9:e1003449
Grover, Harshita Satija; Blanchard, Nicolas; Gonzalez, Federico et al. (2012) The Toxoplasma gondii peptide AS15 elicits CD4 T cells that can control parasite burden. Infect Immun 80:3279-88
Coombes, Janine L; Han, Seong-Ji; van Rooijen, Nico et al. (2012) Infection-induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus. Cell Rep 2:124-35
Dzhagalov, Ivan L; Melichar, Heather J; Ross, Jenny O et al. (2012) Two-photon imaging of the immune system. Curr Protoc Cytom Chapter 12:Unit12.26

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