New typhoid vaccines are urgently required. Salmonella serovars are rapidly developing resistance to antibiotics and licensed vaccines have safety concerns or are pooriy immunogenic. Individuals living in endemic areas often suffer from repeated bouts of typhoid and relapse of primary infection also occurs in 5- 15% of patients. Thus, Salmonella can persist in an immune competent host and acquired immune responses appear unable to completely eradicate infection. Understanding the basis of this immunological problem is critical for the development of effective vaccines against typhoid and is the primary focus of this sub-project. In the previous funding period, we developed a mouse model that allows study of persistent Salmonella shedding, antibiotic-mediated relapsing disease, and the failure to develop robust immunity to this bacterial infection. In this renewal application we propose to study this model in detail and determine the anatomical location of bacteria persistence and develop a detailed understanding of B cells and T cell responses in protective immunity. Our focus on adaptive immunity to enteric and persisting infections provides significant overiap with projects 1 (Lefrancois) and 4 (Cauley).
The specific aims of this sub-project are:
Aim 1. To examine a new model of relapsing Salmonella infection to test thel hypothesis that systemic spread of bacteria initiates from intestinal epithelial cells (lEC).
Aim 2. To visualize Sa/mone//a-specific multifunctional Thi cells and define their role in protection against primary, secondary', and relapsing typhoid.
Aim 3. To visualize Sa/mone//a-specific B cells in vivo and define the role of antibod^ in protection against relapsing infection. Our new preliminary data describe the recent development of state-of-the-art technology to track Sa//T)orje//a-specific lymphocyte responses in vivo, and the generation of ajnovel antibiotic-treatment model to study relapsing typhoid. Our hypothesis is that B and T cells play essential, non-overiapping, roles in bacterial clearance during primary and relapsing Salmonella infection. i

Public Health Relevance

Typhoid kills over 200,000 people every year in developing countries and is recognized as a potential bioterrorist threat in the US. This proposal aims to understand why the adaptive immune response to Salmonella is unable to clear primary infection and allows for persistent and relapsing infection to occur. Understanding these unusual features of host-pathogen interaction will be crucial to the development of effective typhoid vaccines and will expand our understanding of persistent and relapsing bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056172-12
Application #
9268554
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
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

Showing the most recent 10 out of 84 publications