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 Peyer's patches. Numerous studies have described the importance of the interaction between the gastrointestinal pathogen Salmonella Typhimurium and the Peyer's patches, including the observation that Peyer's 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 Peyer's 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 Peyer's patches in an attempt to stimulate a more robust immune response. Following infection with S. Typhi cells targeted to the Peyer's patches, the activation of immune cells in the Peyer's 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.

Public Health Relevance

Effective live attenuated Salmonella Typhi vaccines hold the promise of providing low cost, orally administered, life-long protection against not only typhoid, but a variety of diseases if a heterologous antigen is included. However, while these vaccines are effective in animal models, the results from human trials have been disappointing due to poor immune responses in vaccinees. The goal of this project is to enhance the immunogenicity of live, oral Salmonella Typhi vaccines by targeting the vaccine cells to the immunological tissue of the Peyer's patches for more efficient vaccine uptake and immune stimulation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Alexander, William A
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Arizona State University-Tempe Campus
Other Health Professions
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United States
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