The long-term objectives of this proposal are to understand how the host recognizes and discriminates between microbes that live in distinct cellular compartments, elicits a pathogen-specific immunological response, and generates protective immunity. Listeria monocytogenes is an intracellular bacterium that activates two distinct sets of transcriptional responses in macrophages: a MyD88-dependent response initiated during cell surface and vacuolar recognition and an IRF3-dependent response initiated during cytosolic entry. This bacterium will be used as a model microorganism to determine what role the IRF3- dependent cytosolic response plays during acute infection and long-term immunity. L. monocytogenes mutants that have altered expression of multidrug resistance transporters and consequently induce varying magnitudes of cytosolic gene expression will be exploited to determine the effect of the cytosolic response during infection. The first specific aim will examine the contribution ofthe cytosolic response during acute L. monocytogenes infection in the absence of the TLR-mediated responses. The goal of the second specific aim is to elucidate whether the cytosolic response is involved in dendritic cell maturation and T cell priming. Finally, the third specific aim will address whether the cytosolic response contributes to the generation of T- cell mediated protective immune responses. Uncovering the role of the IRF3-mediated cytosolic response to L. monocytogenes could reveal a new innate immune mechanism important for the generation of protective immunity, knowledge that would be instrumental for vaccine development. The major challenge of vaccine design is how to elicit an immune response that establishes long-term protective immunity against a specific pathogenic microorganism. The research outlined in this proposal will examine how the early inflammatory response to infection with the bacterium Listeria monocytogenes leads to the generation of immunological memory that protects against reinfection. This work will contribute to the understanding of how inflammation generates long-term memory and may reveal new insights on methods to develop safe and effective vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI084333-01
Application #
7749842
Study Section
Special Emphasis Panel (ZRG1-F07-E (20))
Program Officer
Mills, Melody
Project Start
2009-07-17
Project End
2011-07-16
Budget Start
2009-07-17
Budget End
2010-07-16
Support Year
1
Fiscal Year
2009
Total Cost
$47,210
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
Archer, Kristina A; Durack, Juliana; Portnoy, Daniel A (2014) STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes. PLoS Pathog 10:e1003861
Witte, Chelsea E; Archer, Kristina A; Rae, Chris S et al. (2012) Innate immune pathways triggered by Listeria monocytogenes and their role in the induction of cell-mediated immunity. Adv Immunol 113:135-56