Targeting Peyer's Patches To Improve Salmonella Typhi Vaccine Immunogenicity

Project: Research project

Description

The intestinal environment is one in which the host must continually monitor the native bacterial population and evaluate whether any given microbe is friendly and thus should be left alone or is harmful and should be killed. This task is conducted by the mucosal immune system via routine surveillance of the bacterial population by M cells located along the intestine in Peyers patches. Numerous studies have described the importance of the interaction between the gastrointestinal pathogen Salmonella Typhimurium and the Peyers patches, including the observation that Peyers patches are absolutely required to generate mucosal IgA responses to Salmonella. S. Typhimurium preferentially targets this structure for invasion into the host, and invasion results in the production of high levels of pro-inflammatory cytokines, dendritic cell maturation, T cell priming and the initiation of a robust anti-Salmonella immune response. However, this does not occur during infection with S. Typhi, the causative agent of typhoid fever. This has made the development of live attenuated typhoid vaccines difficult, as the immune responses produced by these vaccines are usually weak and short-lived. We have found that S. Typhi is much less efficient at invading Peyers patches than S. Typhimurium, and thus during the initial stages of infection there is significantly less immune involvement. To address this problem, we will use a variety of strategies to deliver S. Typhi bacteria directly to the M cells on the Peyers patches in an attempt to stimulate a more robust immune response. Following infection with S. Typhi cells targeted to the Peyers patches, the activation of immune cells in the Peyers patches, cytokine production and innate immune effector recruitment will all be monitored and compared to the responses observed with untargeted S. Typhi as well as S. Typhimurium. The strategies that are able to increase the level of immune involvement and activation will be applied to currently existing typhoid vaccine platforms as a means to improve their efficacy.
StatusFinished
Effective start/end date7/1/156/30/18

Funding

  • HHS: National Institutes of Health (NIH): $424,875.00

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Salmonella Vaccines
Peyer's Patches
Salmonella typhi
Salmonella typhimurium
Typhoid-Paratyphoid Vaccines
Salmonella
Infection
Population Surveillance
Cytokines
Attenuated Vaccines
Typhoid Fever
Vaccine Immunogenicity
Dendritic Cells
Immunoglobulin A
Intestines
Immune System
Vaccines
Bacteria
T-Lymphocytes