The mucosal immune system is constantly exposed to a wide range of commensal and potentially pathogenic microbial species. This chronic exposure to inflammatory mediators and nonpathogenic organisms makes generation of an appropriate immune response critical in maintaining a balance between elimination of harmful pathogens and regulating responses to nonpathogenic organisms. While Listeria monocytogenes (LM) (a category B Biodefense priority pathogen) is one of the most widely utilized pathogens for examining T cell immune responses, little is known about induction of the mucosal CD8 T cell response after oral infection. The overall hypothesis to be tested is that effector CD8 T cell subsets are differentially regulated by mucosal environmental cues to promote rapid local protection. We will address this hypothesis using a new oral infection model that more closely mimics the human infection.
The specific aims of the project are:
Aim 1 : To define the anatomical events leading to generation of protective mucosal CD8 T cell memory.
Aim 2 : To understand the dynamics of CD8 T cell priming in response to oral bacterial infection.
Aim 3 : To define the mechanisms regulating development of protective mucosal CD8 memory T cells. The studies proposed will examine the eariiest events of CD8 T cell differentiation through memory T cell homeostasis and recall to secondary challenge. Examining the induction of effector T cells and the maintenance and recall of memory T cells to a bona fide gut pathogen that closely mimics human infection is critical for a better understanding of CD8 T cell immunity in the intestinal mucosa. The knowledge gained from this proposal has broad application potential ranging from understanding the immune response to intestinal pathogens to mucosal vaccine designs.

Public Health Relevance

This project will define the parameters controlling the immune response to an intestinal bacterial infection transmitted through ingestion of the pathogen. The mouse model used recapitulates the human infection and therefore has direct relevance to understanding mucosal immunity and vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056172-09
Application #
8728378
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2014
Total Cost
$469,931
Indirect Cost
$136,767
Name
University of Connecticut
Department
Type
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Tsurutani, Naomi; Mittal, Payal; St Rose, Marie-Clare et al. (2016) Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis. J Immunol 196:124-34
Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8
Benoun, Joseph M; Labuda, Jasmine C; McSorley, Stephen J (2016) Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory. MBio 7:
Svedova, Julia; Tsurutani, Naomi; Liu, Wenhai et al. (2016) TNF and CD28 Signaling Play Unique but Complementary Roles in the Systemic Recruitment of Innate Immune Cells after Staphylococcus aureus Enterotoxin A Inhalation. J Immunol 196:4510-21
Romagnoli, Pablo A; Sheridan, Brian S; Pham, Quynh-Mai et al. (2016) IL-17A-producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection. Proc Natl Acad Sci U S A 113:8502-7
Cauley, Linda S (2016) Environmental cues orchestrate regional immune surveillance and protection by pulmonary CTLs. J Leukoc Biol 100:905-912
Romagnoli, P A; Fu, H H; Qiu, Z et al. (2016) Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol :
Cauley, Linda S; Vella, Anthony T (2015) Why is coinfection with influenza virus and bacteria so difficult to control? Discov Med 19:33-40
Colpitts, Sara L; Puddington, Lynn; Lefrançois, Leo (2015) IL-15 receptor α signaling constrains the development of IL-17-producing γδ T cells. Proc Natl Acad Sci U S A 112:9692-7
Pham, Oanh H; McSorley, Stephen J (2015) Protective host immune responses to Salmonella infection. Future Microbiol 10:101-10

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