The factors essential to induction of a protective immune response to bacterial infections are incompletely understood. In the case of Listeria monocytogenes (LM) infection, a category B Priority Pathogen, CD8 T cells are important in effecting sterilizing immunity. LM interfaces at multiple levels with vaccinology as well as the Biodefense initiative due to the significant potential of LM as a vaccine candidate but also as an agent for intentional contamination and generation of highly virulent recombinant strains. Our work has begun to examine the parameters required for effective immunization with killed or mutant LM as potential vaccine vehicles. Specifically, immunization with heat killed LM (HKL) or irradiated LM (IRL) induced distinct patterns of T cell activation characterized by much more robust CD8 T cell memory induction following vaccination with IRL. However, IRL immunization did not induce the level of T cell activation and memory induction obtained with live LM infection. Thus, this is an excellent system for delineation of the mechanisms involved in promotion of distinct degrees of CD8 T cell activation generated by distinct forms of the same pathogen. Based on our preliminary data, the newly proposed studies focus on integrating the anatomy of effective CD8 T cell immune response initiation and memory T cell reactivation with the costimulatory and genetic programming necessary to drive a protective immune response. The hypothesis that responses induced by live infection versus immunization with attenuated vaccines share common essential components to generate protective memory will be tested in three aims:
Specific Aim 1. To determine the role of costimulation and CD4 T cell help in priming and protective recall responses following LM infection or vaccination.
Specific Aim 2. To determine the anatomical features of effective CD8 T cell vaccination and recall responses.
Specific Aim 3. To define the genetic signature of responding CD8 T cells in response to effective vaccination.

Public Health Relevance

The goal of this proposal is to determine the reasons why some vaccines are more effective than others. By studying different forms of a bacterial vaccine, our studies will help us devise more effective vaccination strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076457-05
Application #
8389673
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Mills, Melody
Project Start
2008-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$340,880
Indirect Cost
$110,556
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Bose, Tina O; Colpitts, Sara L; Pham, Quynh-Mai et al. (2014) CD11a is essential for normal development of hematopoietic intermediates. J Immunol 193:2863-72
Sheridan, Brian S; Pham, Quynh-Mai; Lee, Young-Tae et al. (2014) Oral infection drives a distinct population of intestinal resident memory CD8(+) T cells with enhanced protective function. Immunity 40:747-57
Colpitts, Sara L; Stonier, Spencer W; Stoklasek, Thomas A et al. (2013) Transcriptional regulation of IL-15 expression during hematopoiesis. J Immunol 191:3017-24
Xu, Daqi; Fu, Han-Hsuan; Obar, Joshua J et al. (2013) A potential new pathway for PD-L1 costimulation of the CD8-T cell response to Listeria monocytogenes infection. PLoS One 8:e56539
Bose, Tina O; Pham, Quynh-Mai; Jellison, Evan R et al. (2013) CD11a regulates effector CD8 T cell differentiation and central memory development in response to infection with Listeria monocytogenes. Infect Immun 81:1140-51
Plumlee, Courtney R; Sheridan, Brian S; Cicek, Basak B et al. (2013) Environmental cues dictate the fate of individual CD8+ T cells responding to infection. Immunity 39:347-56
Turner, Damian L; Bickham, Kara L; Farber, Donna L et al. (2013) Splenic priming of virus-specific CD8 T cells following influenza virus infection. J Virol 87:4496-506
Sheridan, Brian S; Romagnoli, Pablo A; Pham, Quynh-Mai et al. (2013) ýýýý T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39:184-95
Obar, Joshua J; Jellison, Evan R; Sheridan, Brian S et al. (2011) Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol 187:4967-78
Teijaro, John R; Turner, Damian; Pham, Quynh et al. (2011) Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol 187:5510-4

Showing the most recent 10 out of 21 publications