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 #
5R01AI076457-09
Application #
9184533
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Mills, Melody
Project Start
2008-12-01
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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 :
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
Sheridan, Brian S; Obar, Joshua J (2016) Editorial: V?9V?2 T cells: triple costimulation goes the distance. J Leukoc Biol 99:515-7
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
Obar, Joshua J; Sheridan, Brian S (2015) Tracking cytotoxic potential in vivo. Cell Mol Immunol 12:505-7
Bose, Tina O; Colpitts, Sara L; Pham, Quynh-Mai et al. (2014) CD11a is essential for normal development of hematopoietic intermediates. J Immunol 193:2863-72
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
Xu, Daqi; Fu, Han-Hsuan; Obar, Joshua J et al. (2013) A potential new pathway for PD-L1 costimulation of the CD8-T cell response to Listeria monocytogenes infection. PLoS One 8:e56539
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

Showing the most recent 10 out of 33 publications