The goal of this project is to determine how the immune response to Listeria monocytogenes is regulated by activation of antigen presenting cells. Listeria trigger APC activation through a network of pattern recognition receptors and signaling adapters. Signals transduced upon cytoplasmic entry are required for virulence of the bacteria and for development of protective immunity. Likewise, signaling through the Toll-like receptor adapter MyD88 is essential for a significant portion of the DC maturation response induced by listerial infection. We have identified many of the key molecules induced in DC by listerial cytoplasmic entry. We determined that the expression of costimulatory molecules and inflammatory cytokines by DC was dependent upon expression of the hemolysin, LLO and bacterial cytoplasmic entry. We have also determined the role of each of these molecules in priming CD8+ T cell proliferation and function. We will now explore the molecular basis for DC maturation induced by Listeria by examining the role of Toll-like receptors, TLR adapters, and cytosolic receptors with the studies proposed in Specific Aim 1. We will also determine the role of these molecules in generating protective immunity to Listeria using Listeria-infected DC as an immunogen in vivo. We will then determine the role of costimulatory molecules and cytokines induced by listerial infection in the formation of the immunological synapse with the studies proposed in specific aim 2. These novel studies will reveal how the interaction of T cells with infected antigen presenting cells gives rise to protective T cell responses. Our studies will provide important insights into the interaction of this intracellular bacteria with the host immune system and will aid the design of efficacious vaccines against this pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057770-05
Application #
7560374
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Mills, Melody
Project Start
2005-02-15
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$333,696
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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