Enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi) poses a significant threat to public health, and is responsible for an estimated 21 million illnesses and 200,000 deaths annually. Increasing antibiotic resistance among S. Typhi isolates has further exacerbated the threat from this infectious agent. To develop improved broad spectrum vaccines against S. Typhi, a better understanding of host immune responses that are responsible for protection is necessary. The role ofthe resident gut microbiota in this process is only now just beginning to be explored, even though it has been established that certain members ofthe gut microbiota are intimately linked to mucosal immunity. Previous studies from Drs. Fraser and Sztein carried out under the current CCHI funding have shown that multi-phasic CMI responses following immunization with oral, live-attenuated S. Typhi correlate with the presence of a high diversity gut microbiota, and that over two hundred members within the order Clostridiales differentiate multi-phasic and late responders. A human challenge model of wild-type (wt) S. Typhi infection has recently been established by the Oxford Vaccine Group, and a study has been performed to determine the protective efficacy of the licensed oral, live-attenuated vaccineTy21a and the novel ZH9 vaccine candidate using this model. We propose an innovative and integrative study that will leverage the availability of these samples to characterize the structure and function of the gut microbiota following exposure to S. Typhi and will allow us to further investigate the central hypothesis that mucosal immune responses (to be determined in Research Project 1) are intimately linked to the gut microbiota and, that together, these might determine susceptibility to or protection from typhoid disease. The results from this project will be validated using in vitro systems in Research Project 3. In addition, we will also test the hypothesis that robust immune responses in children immunized with Ty21a correlate with the presence of a high diversity gut microbiota. Immune data and microbiome data will be integrated in collaboration with the Bioinformatics and Biostatics Core to provide a holistic view of the interplay between the mucosal immune system and the gut microbiota.

Public Health Relevance

The goal of the proposed work in this application is to examine the interplay between the mucosal immune system, the gut microbiota, and response to a high-priority enteric pathogen, S. Typhi. This work will take advantage of human wt S. Typhi challenge studies and will advance our understanding of host-pathogen-microbiota interactions.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082655-06
Application #
8726149
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
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, Rosangela; Rezwan, Tasmia; Sztein, Marcelo B (2014) B cells modulate mucosal associated invariant T cell immune responses. Front Immunol 4:511
Fiorentino, Maria; Levine, Myron M; Sztein, Marcelo B et al. (2014) Effect of wild-type Shigella species and attenuated Shigella vaccine candidates on small intestinal barrier function, antigen trafficking, and cytokine release. PLoS One 9:e85211
Waddington, Claire S; Darton, Thomas C; Jones, Claire et al. (2014) An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis 58:1230-40
Wahid, Rezwanul; Zafar, Shah J; McArthur, Monica A et al. (2014) Live oral Salmonella enterica serovar Typhi vaccines Ty21a and CVD 909 induce opsonophagocytic functional antibodies in humans that cross-react with S. Paratyphi A and S. Paratyphi B. Clin Vaccine Immunol 21:427-34
McArthur, Monica A; Sztein, Marcelo B; Edelman, Robert (2013) Dengue vaccines: recent developments, ongoing challenges and current candidates. Expert Rev Vaccines 12:933-53
Eloe-Fadrosh, Emiley A; McArthur, Monica A; Seekatz, Anna M et al. (2013) Impact of oral typhoid vaccination on the human gut microbiota and correlations with s. Typhi-specific immunological responses. PLoS One 8:e62026
Barry, Eileen M; Pasetti, Marcela F; Sztein, Marcelo B et al. (2013) Progress and pitfalls in Shigella vaccine research. Nat Rev Gastroenterol Hepatol 10:245-55
Eloe-Fadrosh, Emiley A; Rasko, David A (2013) The human microbiome: from symbiosis to pathogenesis. Annu Rev Med 64:145-63
McArthur, Monica A; Sztein, Marcelo B (2013) Unexpected heterogeneity of multifunctional T cells in response to superantigen stimulation in humans. Clin Immunol 146:140-52
Wahid, Rezwanul; Simon, Jakub K; Picking, Wendy L et al. (2013) Shigella antigen-specific B memory cells are associated with decreased disease severity in subjects challenged with wild-type Shigella flexneri 2a. Clin Immunol 148:35-43

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