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.
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.
|Haney, Douglas J; Lock, Michael D; Gurwith, Marc et al. (2018) Lipopolysaccharide-specific memory B cell responses to an attenuated live cholera vaccine are associated with protection against Vibrio cholerae infection. Vaccine 36:2768-2773|
|Davis, Courtney L; Wahid, Rezwanul; Toapanta, Franklin R et al. (2018) A clinically parameterized mathematical model of Shigella immunity to inform vaccine design. PLoS One 13:e0189571|
|Toapanta, Franklin R; Bernal, Paula J; Kotloff, Karen L et al. (2018) T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans. J Transl Med 16:61|
|Zhang, Yan; Brady, Arthur; Jones, Cheron et al. (2018) Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi. MBio 9:|
|Senger, Stefania; Ingano, Laura; Freire, Rachel et al. (2018) Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC). Cell Mol Gastroenterol Hepatol 5:549-568|
|Sztein, Marcelo B (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? CD8 T-Cell-Mediated Protective Immunity and Vaccination against Enteric Bacteria. Cold Spring Harb Perspect Biol 10:|
|Salerno-Gonçalves, Rosângela; Tettelin, Hervé; Lou, David et al. (2017) Use of a novel antigen expressing system to study the Salmonella enterica serovar Typhi protein recognition by T cells. PLoS Negl Trop Dis 11:e0005912|
|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|
|Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence S et al. (2017) Importance ofSalmonellaTyphi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol 8:208|
|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|
Showing the most recent 10 out of 59 publications