Listeria monocytogenes (LM) (a category 2 Biodefense pathogen) is being developed as a vaccine vehicle for combating infection as well as cancer. Such vaccines may have particular utility against mucosal pathogens as well as against tumors since robust CD4 and CD8 T cell responses are induced by LM infection. In addition, recombinant LM expressing heterologous proteins have potential as vaccines against a variety of systemic or mucosal infections by inducing other protective mechanisms, such as antibody responses. The overarching hypothesis to be tested in this proposal is that a complex interplay between regulatory and inflammatory signals will result in distinct cellular and humoral outcomes during an adaptive immune response in the intestinal mucosa that will affect immunity at other sites. Although much has been learned in recent years with regard to the T cell response to infection, particularly using systemically administered LM, little is known regarding the intestinal mucosal immune response to oral infection, the natural infection route for this and many other human pathogens. What studies have been done used wild-type (WT) LM, which is a human- derived strain, to infect mice. This is an issue since WT internalin A, the receptor that binds to intestinal epithelial cell E-cadherin (E-cad) to allow bacterial invasion, has high affiniy for human E-cad but binds poorly to mouse E-cad. This proposal utilizes a newly developed recombinant LM expressing a modified internalin A protein (InlAM rLM) that binds mouse E-cad with high affinity, thereby allowing infection of the intestinal epithelium and subsequent bacteria dissemination. Thus, the immune response to LM immunization can now be studied in a natural setting more closely paralleling human infection. We will use this system to determine the efficacy of InlAM rLM vaccination to protect against homologous and heterologous infections and to dissect the contribution of migrating and tissue resident memory T cells in mediating protection in the intestine or lung in three specific aims:
Aim 1 : Determine the functional outcome of LM vaccination.
Aim 2 : Determine the efficacy of oral LM vaccination in protection against homologous and heterologous infections.
Aim 3 : To determine the contribution of mucosal memory T cell subsets to secondary protection against challenge infections.

Public Health Relevance

These studies are highly relevant to the design and implementation of mucosal vaccines. This work will reveal new features of the gastrointestinal mucosal immune system which is critically important in understanding the control of gut infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI076457-06A1
Application #
8818260
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Mills, Melody
Project Start
2008-12-01
Project End
2014-12-31
Budget Start
2014-12-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
Qiu, Zhijuan; Khairallah, Camille; Sheridan, Brian S (2018) Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response. Pathogens 7:
Qiu, Zhijuan; Sheridan, Brian S (2018) Isolating Lymphocytes from the Mouse Small Intestinal Immune System. J Vis Exp :
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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
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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

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