Enteric infections are endemic and epidemic infectious diseases that still afflict major populations around the world, particularly in developing nations, and also pose risks for US travelers (including deployed military personnel). Vaccines are widely viewed as cost-effective interventions to prevent and control endemic and epidemic infections. In spite of the need to develop new or improved vaccines against enteric pathogens of great public health importance, their development has been impeded by fragmentary understanding of the immunological mechanisms operational systemically and in the complex environment of the Gl tract. Thus, the central theme of this proposed CCHI is to advance our knowledge of human mucosal Immunity. To this end we will address the overarching hypothesis that the delicate homeostasis of effector and regulatory Immunological mechanisms elicited systemically and In the gut mucosa, and the Interplay with the resident gut microbiota, play a critical role In protection from typhoid fever In humans. Some of the unique resources to be utilized are specimens already collected during ground-braking clinical trials involving the challenge of volunteers with wild-type (wt) S. Typhi before or following immunization with attenuated S. Typhi vaccines, including the FDA licensed Ty21 a typhoid vaccine. In addition to sophisticated mechanistic immunological studies, because evidence is rapidly accumulating that the normal microbiota is likely to play a major role in the induction of host's immune responses, we propose to dramatically expand the pioneering studies conducted during the current CCHI grant on the interactions between the host immune responses and the gut microbiota in humans. Equally important, we will utilize state-of-the-art sophisticated in vitro organotypic models of the human intestinal mucosa and mucosal biopsy explants to study the initial interactions between S. Typhi and the host, including innate immunity and physiological consequences. Finally, we will perform studies in children, who are primarily affected by typhoid fever but for whom virtually no information is available on the protective immunity elicited by Ty21a immunization. Because of the complexity of this undertaking, we have assembled a multidisciplinary team consisting of renowned investigators in the fields of innate and adaptive immunity, vaccinology, mucosal biology and physiology, clinical gastroenterology (with extensive experience in performing endoscopies), molecular biology, biochemistry, microbiology, genomics, bioinformatics and biostatistics. We expect this CCHI to yield much needed information in an area of great importance to human health and to advance the development of much needed improved oral vaccines.

Public Health Relevance

Development of improved vaccines to the human-restricted pathogen S. Typhi and other organisms is impeded by limited knowledge ofthe determinants of systemic and mucosal protective immunity. Similarly, little is known on the likely major role that the microbiota has on the human immune response and the consequences ofthe initial S. Typhi-human intestinal mucosa interactions on innate immunity and gut physiology. We will address these wide gaps in knowledge to advance the development of much needed vaccines for human use which can be administered orally.

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 #
8726150
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
McArthur, Monica A; Chen, Wilbur H; Magder, Laurence et al. (2017) Impact of CD4+ T Cell Responses on Clinical Outcome following Oral Administration of Wild-Type Enterotoxigenic Escherichia coli in Humans. PLoS Negl Trop Dis 11:e0005291
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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