This renewal of the program project """"""""Modulation of biodefense responses to microbial pathogens"""""""" is composed of four projects and three cores focused on the immune response to Category B and C Biodefense Pathogens and their products. The central hypothesis is that early events during activation of the mucosal innate and adaptive immune responses determine whether or not immunity or injury is induced in response to infection, or bacterial toxin exposure, respectively. Each project focuses on a unique aspect of the theme to advance our overall understanding of the mucosal immune response to infectious agents or their toxins. Since human disease can be easily spread by deliberate or accidental contamination of food, water, or air, our focus is on mucosal tissues at the interface with environmental exposure. Project 1 (Lefrancois) proposes to investigate the mechanisms regulating the intestinal mucosal T cell response to oral Listeria monocytogenes infection (LM). A novel system that mimics human infection will be employed. Project 2 (McSorley) will examine a new model of relapsing Salmonella infection and will define the critical requirements to elicit protective immunity. Project 3 (Vella) will determine how pulmonary administration of Staphylococcus aureus enterotoxin mediates acute lung injury. An innovative proteomic mining strategy will be used to test the novel hypothesis that T cell responses against enterotoxins guide a cell damage process that manifests in profound lung pathology. Project 4 (Cauley) will investigate the mechanisms that support sustained cellular immunity in the lungs against influenza virus infection. The projects utilize in vivo models, in-depth cellular immunological techniques and state-of-the-art imaging and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy. The projects and cores synergistically interact and mutually reinforce one another to achieve the goals of the program. Coupled with strong institutional support, it is anticipated that significant new insights in immune response regulatio to pathogens and their byproducts will continue to be obtained.

Public Health Relevance

The work performed under this Program has direct relevance to the development of vaccines and countermeasures for protection against viral and bacterial pathogens and their products. The studies described will provide an in-depth understanding of how productive and sometimes destructive mucosal immune responses are induced and controlled.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056172-09
Application #
8661689
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Program Officer
Miller, Lara R
Project Start
2003-09-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2014
Total Cost
$2,660,765
Indirect Cost
$774,380
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Romagnoli, P A; Fu, H H; Qiu, Z et al. (2017) Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol 10:520-530
Liu, Wenhai; Menoret, Antoine; Vella, Anthony T (2017) Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2. Cell Mol Immunol 14:254-253
Shinde, Paurvi; Liu, Wenhai; Ménoret, Antoine et al. (2017) Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production. J Leukoc Biol 102:57-69
Pham, Oanh H; O'Donnell, Hope; Al-Shamkhani, Aymen et al. (2017) T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS Pathog 13:e1006566
Lee, Seung-Joo; Benoun, Joseph; Sheridan, Brian S et al. (2017) Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells. J Immunol 199:1353-1361
Risso, Gabriela S; Carabajal, Marianela V; Bruno, Laura A et al. (2017) U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice. Front Immunol 8:171
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
Cauley, Linda S (2016) Environmental cues orchestrate regional immune surveillance and protection by pulmonary CTLs. J Leukoc Biol 100:905-912
Romagnoli, Pablo A; Sheridan, Brian S; Pham, Quynh-Mai et al. (2016) IL-17A-producing resident memory ?? T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection. Proc Natl Acad Sci U S A 113:8502-7

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