The overall aim of this proposal is to understand the role of NF-kB in the regulation of the immune response to Toxoplasma gondii. T. gondii is an opportunistic pathogen in patients with acquired and primary deficiencies in cell mediated immunity. Resistance to this pathogen is based on the production of IL-12 which is required for NK and T cell production of IFN-g the major mediator of resistance to T. gondii. The NF-icB proteins are a family of transcription factors associated with many of the events that lead to the production of IFN-g required for resistance to T. gondii. For example, NF-icB is associated with the production of IL-12, and the ability of IL-12 to stimulate the production of IFN-'y is dependent on co-factors, such as IL-18 and CD28, which activate NF-kB. Thus, NF-kB is likely to be involved in resistance to T. gondii. Our studies have shown that infection with T. gondii leads to activation of NF-icB and that two members of this family, c-Rel and Rem, are required for optimal production of IFN-g. Additional studies using a transgenic mouse which expresses a specific inhibitor of NF-icB in 'I cells, indicates that the activation of NF-kB in I cells is required for the development of protective IFN-g responses. Based on these preliminary studies, we propose to perform studies which address the molecular and cellular basis for the role of NF-kB in the development of IFN-g responses. The proposed studies will not only provide a mechanism for why mice deficient in NF-kB mediated signaling are susceptible to toxoplasmosis, but will also provide novel insights into the mechanisms that lead to the production of IFN-g, a cytokine critical for resistance to many of the opportunistic infections which affect patients with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046288-02
Application #
6510923
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Wali, Tonu M
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$237,750
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Masek, K S; Zhu, P; Freedman, B D et al. (2007) Toxoplasma gondii induces changes in intracellular calcium in macrophages. Parasitology 134:1973-9
Tato, Cristina M; Mason, Nicola; Artis, David et al. (2006) Opposing roles of NF-kappaB family members in the regulation of NK cell proliferation and production of IFN-gamma. Int Immunol 18:505-13
Masek, Katherine S; Fiore, Jim; Leitges, Michael et al. (2006) Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii. J Cell Sci 119:4565-73
Sun, Jie; Walsh, Matthew; Villarino, Alejandro V et al. (2005) TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development. J Immunol 174:742-51
Artis, David; Kane, Colleen M; Fiore, James et al. (2005) Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation. J Immunol 174:7154-9
Tato, Cristina M; Martins, Gislaine A; High, Frances A et al. (2004) Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter. J Immunol 173:1514-7
Kane, Colleen M; Cervi, Laura; Sun, Jie et al. (2004) Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol 173:7454-61
Mason, Nicola J; Fiore, Jim; Kobayashi, Takashi et al. (2004) TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii. Infect Immun 72:5662-7
Mason, Nicola J; Liou, Hsiou-Chi; Hunter, Christopher A (2004) T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to Toxoplasma gondii. J Immunol 172:3704-11
Mason, Nicola J; Artis, David; Hunter, Christopher A (2004) New lessons from old pathogens: what parasitic infections have taught us about the role of nuclear factor-kappaB in the regulation of immunity. Immunol Rev 201:48-56

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