The intestinal epithelium presents the largest mucosal barrier between the internal host milieu and the external environment. Under physiological circumstances antigen trafficking occurs through three nonmutually exclusive pathways: transcellular, paracellular, and dendritic cell sampling within the intestinal lumen. When the delicate balance between controlled antigen trafficking and host immune response is lost, severe inflammation and overt clinical symptoms may develop. This negative outcome may be influenced by host genetic makeup, virulence traits of the intestinal pathogens, or the combination of both. The outcome of the interplay between host and intestinal microorganisms is influenced by the fact that the intestinal epithelium is extremely dynamic and exquisitely responsive to stimuli of innumerable variety and it is populated by a complex climax community of microbial partners, far more numerous than the cells of the intestine itself. In normal homeostasis, the gastrointestinal epithelial layer forms a tight, but selective barrier: microbes and most antigens are held at bay, but nutrients from the essential to the trivial are absorbed efficiently. Moreover, the tightness of the epithelial barrier is itself dynamic and depends on tight junctions (TJ) competency, though the mechanisms governing and affecting their permeability are poorly understood. What is becoming increasingly clear is that defects in epithelial permeability are associated with a large number of local and even systemic disorders. A common feature of enteric infections is their ability to increase epithelial permeability, an effect that initiates and promotes the host immune response. Mucosal permeability is also a factor in the delivery of mucosally introduced vaccines. With this project, we intend to capitalize on our combined expertise in mucosal biology, proteomics, genomics, microbiomics, biochemistry, and molecular biology to determine the role of alterations in mucosal barrier function in host-microbial interactions affecting antigen trafficking that lead to local and systemic immune responses to gastric and enteric pathogens. We will take full advantage of a very conducive environment that includes the Mucosal Biology Research Center, the Center for Vaccine Development and The Institute of Genomic Science, all thematically relevant to this proposal.

Public Health Relevance

The studies proposed in this project will shed light on the enteric pathogen/intestinal mucosa interaction mediated by pattern recognition receptors leading to altered antigen trafficking and local and/or systemic immune responses. Subtraction analysis between wild type strains and correspondent vaccine candidates will assist us in designing better live, attenuated vaccines to prevent enteric infections and systemic diseases

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082655-04
Application #
8378486
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$283,194
Indirect Cost
$88,577
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Booth, Jayaum S; Patil, Seema A; Ghazi, Leyla et al. (2017) Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans. Cell Mol Gastroenterol Hepatol 4:419-437
Salerno-Goncalves, Rosângela; Luo, David; Fresnay, Stephanie et al. (2017) Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol 8:398
Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence S et al. (2017) Importance of Salmonella Typhi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol 8:208
Arevalillo, Jorge M; Sztein, Marcelo B; Kotloff, Karen L et al. (2017) Identification of immune correlates of protection in Shigella infection by application of machine learning. J Biomed Inform 74:1-9
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
Toapanta, Franklin R; Bernal, Paula J; Fresnay, Stephanie et al. (2016) Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis 10:e0004766
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
Cong, Yu; McArthur, Monica A; Cohen, Melanie et al. (2016) Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells. PLoS Negl Trop Dis 10:e0004709
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

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