Abstract

Listeria monocytogenes (LM) infection generates a robust innate and adaptive immune response. As a result, several attenuated stains of recombinant LM are being investigated as vaccine vehicles. However, compared to infection with live-LM, immunization with attenuated or killed LM vaccines fails to induce protective cell mediated immunity. Potent activation of the innate immune response is necessary for the robust priming and differentiation of a protective CD8 T cell response. The precise cellular mechanisms that drive a productive vs. a poorly-productive immune response are not well understood. Mounting a protective immune response is dependent on the orchestrated movement of cells within lymphoid organs. This movement is carefully regulated by several factors including host-pathogen interactions and the highly organized lymphoid structure. The cellular mechanisms that control the temporal events that lead to the robust activation of the innate immune system that subsequently induce pathogen-specific cell mediated immunity are poorly understood. In particular, the role of host-pathogen interactions and their geographical localization within a lymphoid organ is poorly defined. Understanding how pathogens interact with immune cells in vivo is important to develop effective and safe microbial based vaccines. Here, we will use distinct immunization models to test the overall hypothesis that changes in the cellular niche of Listeria control the temporal compartmentalization of the bacteria in the spleen. The splenic localization of LM in turn regulates innate immune cell recruitment, local migration and differentiation. The proper progression of these hierarchical events ultimately dictates the outcome of the protective adaptive immunity rendered against the pathogen. In this proposal we will visualize an effective vs. an ineffective anti-microbial immune response with the goal of identifying the pivotal checkpoint(s) of an immune response that lead to protective immunity in vivo. Based on our preliminary data and published studies we propose the following aims: 1) To determine the cellular tropism, localization and antigen presentation after immunization with live-LM or attenuated LM strains. 2) To determine the anatomical mechanisms surrounding ineffectual vaccination. 3) To Determine the cellular mechanisms for the splenic trafficking of live-LM and bacterial antigens in vivo.

Public Health Relevance

This proposal will utilize a diverse and innovative experimental strategy to uncover the innate and adaptive immune mechanisms in vivo that contribute to a productive versus an unproductive immune response to bacterial infections. These kinds of analyses have direct implications for understanding and modulating immunity and will likely lead to improving vaccine design.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097375-03
Application #
8605831
Study Section
Immunity and Host Defense (IHD)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2012-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

Grenier, Jeremy M; Yeung, Stephen T; Khanna, Kamal M (2018) Combination Immunotherapy: Taking Cancer Vaccines to the Next Level. Front Immunol 9:610
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
Perez, Oriana A; Yeung, Stephen T; Vera-Licona, Paola et al. (2017) CD169+ macrophages orchestrate innate immune responses by regulating bacterial localization in the spleen. Sci Immunol 2:
Benechet, Alexandre P; Menon, Manisha; Xu, Daqi et al. (2016) T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection. Proc Natl Acad Sci U S A 113:2182-7
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
Qiu, Zhijuan; Cervantes, Jorge L; Cicek, Basak B et al. (2016) Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4. Sci Rep 6:31936
Qiu, Zhijuan; Huang, Huakang; Grenier, Jeremy M et al. (2015) Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8(+) T-cell Response and Protects Mice from Melanoma. Cancer Immunol Res 3:536-46
Sharma, Naveen; Benechet, Alexandre P; Lefrançois, Leo et al. (2015) CD8 T Cells Enter the Splenic T Cell Zones Independently of CCR7, but the Subsequent Expansion and Trafficking Patterns of Effector T Cells after Infection Are Dysregulated in the Absence of CCR7 Migratory Cues. J Immunol 195:5227-36
Hill, Timothy M; Gilchuk, Pavlo; Cicek, Basak B et al. (2015) Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease. PLoS Pathog 11:e1004975
Fujiwara, Mai; Anstadt, Emily J; Khanna, Kamal M et al. (2015) Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720. Clin Immunol 158:103-13

Showing the most recent 10 out of 12 publications