Enteric infections, including typhoid fever, are a major source of morbidity and mortality worldwide. The lack of information regarding the immunological correlates of protection against these organisms in humans has hindered the greatly needed development of new and improved vaccines against these important pathogens. The availability of unique specimens from subjects immunized and/or challenged with wild-type (wt) Salmonella enterlca serovar Typhi (S. Typhi), as well as specimens from subjects immunized with the licensed Ty21a oral typhoid vaccine in conjunction with novel technologies and instrumentation (e.g., mass flow cytometry) provide an unprecedented opportunity to investigate the key immunological responses involved in protection at both the systemic and mucosal levels. Our overarching hypothesis is that the delicate homeostasis between the effector and regulatory arms of the immune system, both systemically and in the gut mucosa, plays a critical role in protection from typhoid fever in humans. To begin to understand the complex interaction of various cell subsets of the systemic and mucosal immune systems that may play a role in protection against S. Typhi in humans, we will evaluate the following hypotheses: (1) Protection from S. Typhi disease in a human challenge model is determined by the balance of effector and regulatory responses;(2) Protection induced by immunization with attenuated S. Typhi strains is determined by the balance of effector and regulatory responses;(3) Increased levels of mucosa-associated invariant T (MAIT) cell activation and exhaustion following exposure to S. Typhi antigens contributes to the development of typhoid fever;and (4) Oral vaccination with Ty21a elicits immune responses at the mucosal and systemic levels that differ in magnitude and characteristics. Furthermore, we will integrate the immunological data generated in this project with the composition and functional properties of the gut microbiota (Research Project 2) and the mechanistic studies of mediators of protection at the mucosal level in an in vitro 3-D bioengineered human intestinal tissue model (Research Project 3). These studies will address critical gaps in knowledge and provide the most comprehensive investigation of the correlates of protection against S. Typhi to date which may also be broadly applicable to other enteric pathogens.

Public Health Relevance

The goal of the studies proposed in this application is to identify the immunological correlates of protection against S. Typhi, a human enteric pathogen of great public health significance. This work will take advantage of unique human specimens (including a wild-type S. Typhi human challenge model) and novel technologies and instrumentation to advance our understanding of the systemic and mucosal immune responses responsible for protection against S. Typhi.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082655-06
Application #
8726148
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Salerno-Goncalves, R; Safavie, F; Fasano, A et al. (2016) Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses. Clin Exp Immunol 185:338-47
Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence et al. (2016) Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. J Transl Med 14:62
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77
Salerno-Goncalves, Rosangela; Fasano, Alessio; Sztein, Marcelo B (2016) Development of a Multicellular Three-dimensional Organotypic Model of the Human Intestinal Mucosa Grown Under Microgravity. J Vis Exp :
McArthur, Monica A; Fresnay, Stephanie; Magder, Laurence S et al. (2015) Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model. PLoS Pathog 11:e1004914
Trebicka, Estela; Shanmugam, Nanda Kumar N; Chen, Kejie et al. (2015) Intestinal Inflammation Leads to a Long-lasting Increase in Resistance to Systemic Salmonellosis that Requires Macrophages But Not B or T Lymphocytes at the Time of Pathogen Challenge. Inflamm Bowel Dis 21:2758-65
Wahid, R; Fresnay, S; Levine, M M et al. (2015) Immunization with Ty21a live oral typhoid vaccine elicits crossreactive multifunctional CD8+ T-cell responses against Salmonella enterica serovar Typhi, S. Paratyphi A, and S. Paratyphi B in humans. Mucosal Immunol 8:1349-59
Booth, Jayaum S; Salerno-Goncalves, Rosangela; Blanchard, Thomas G et al. (2015) Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection. Front Immunol 6:466
Toapanta, Franklin R; Bernal, Paula J; Fresnay, Stephanie et al. (2015) Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis 9:e0003837
Sztein, Marcelo B; Salerno-Goncalves, Rosangela; McArthur, Monica A (2014) Complex adaptive immunity to enteric fevers in humans: lessons learned and the path forward. Front Immunol 5:516

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