The long-term objectives of our study are to understand 1) what bacterial antigens are recognized by the immune system and what factors influence the repertoire of antigenic targets in bacteria, 2) what immune mechanisms are protective and how host immune effectors counteract specific virulence factors to bring about protective immunity, and 3) how likely and by what mechanisms bacteria may escape immune surveillance. In this application, we will use Listeria monocytogenes (LM) as a model to: 1. Examine how regulation of gene expression affects the ability of a bacterial protein to induce immune responses and to serve as a protective target. The results of this study will help us define the complexity of the antigenic repertoire of bacteria and develop general guidelines for the selection of antigenic targets for vaccination. 2. Test a model that protective immunity against LM is determined by a race between CTL-mediated cytolysis and bacterial spread into neighboring cells. This model is suggested by our finding that CTL cytolysis functions to counteract LM's virulence strategy of direct cell-cell spread. We will test several predictions of this model and in doing so we hope to identify mechanisms of immune protection that correlate with bacterial virulence strategies. 3. Investigate the possibility that antagonist peptides may play a role in shaping the repertoire of T cell targets and in allowing bacterial escape of CTL surveillance. Our preliminary results have demonstrated the in vivo effect of TCR antagonism on T cell responses and protective immunity. We will study several aspects of agonist/antagonist interactions in vivo during infection. The results of these studies will help in our understanding of the complex interactions between bacteria and their hosts that determine the outcome of infection, and will have important implications for the design of effective vaccines and the selection of protective vaccine antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045025-08
Application #
7009364
Study Section
Special Emphasis Panel (ZRG1-BM-1 (05))
Program Officer
Mills, Melody
Project Start
1999-02-15
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
8
Fiscal Year
2006
Total Cost
$329,131
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dispirito, Joanna R; Shen, Hao (2010) Histone acetylation at the single-cell level: a marker of memory CD8+ T cell differentiation and functionality. J Immunol 184:4631-6
Northrop, John K; Wells, Andrew D; Shen, Hao (2008) Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J Immunol 181:865-8
Zenewicz, Lauren A; Shen, Hao (2007) Innate and adaptive immune responses to Listeria monocytogenes: a short overview. Microbes Infect 9:1208-15
Pearce, Erika L; Shen, Hao (2007) Generation of CD8 T cell memory is regulated by IL-12. J Immunol 179:2074-81
Ekkens, Melinda J; Shedlock, Devon J; Jung, Euihye et al. (2007) Th1 and Th2 cells help CD8 T-cell responses. Infect Immun 75:2291-6
Krawczyk, Connie M; Shen, Hao; Pearce, Edward J (2007) Functional plasticity in memory T helper cell responses. J Immunol 178:4080-8
Krawczyk, Connie M; Shen, Hao; Pearce, Edward J (2007) Memory CD4 T cells enhance primary CD8 T-cell responses. Infect Immun 75:3556-60
Foulds, Kathryn E; Shen, Hao (2006) Clonal competition inhibits the proliferation and differentiation of adoptively transferred TCR transgenic CD4 T cells in response to infection. J Immunol 176:3037-43
Northrop, John K; Thomas, Rajan M; Wells, Andrew D et al. (2006) Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells. J Immunol 177:1062-9
Zenewicz, Lauren A; Wei, Zhengyu; Goldfine, Howard et al. (2005) Phosphatidylinositol-specific phospholipase C of Bacillus anthracis down-modulates the immune response. J Immunol 174:8011-6

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