The adaptive immune response to mucosal pathogens is still poorly understood, limiting the development of new vaccines for important human pathogens such as the category B bioterrorism agent Salmonella. We propose to use newly developed reagents to examine the priming of Salmonella-specific CD4 T cells in the intestinal mucosa and systemic tissues, explore the mechanism of effector cytokine production in the infected liver, and examine the effect of bacteria on the survival of Salmonella- specific T cells in vivo.
The specific aims of this proposal are:
Aim 1. Test the hypothesis that bacterial antigen expression shapes the Salmonella-specific CD4 repertoire at mucosal and systemic sites.
Aim 2. Test the hypothesis that innate activation of Salmonella-specific CD4 T cells amplifies effector cytokine production in infected tissues.
Aim 3. Test the hypothesis that live Salmonella can inhibit survival of activated CD4 T cells via SPI2 effector proteins. Our preliminary data demonstrate that we have identified several new targets of Salmonella-specific CD4 T cells and can develop novel MHC class-II tetramer reagents to track the mucosal and systemic Salmonella-specific T cell response in vivo. Our data also demonstrate that previously activated CD4 T cells can be activated by innate stimuli without TCR ligation. Lastly our preliminary data indicate that live bacteria inhibit the survival of Salmonella-specific T cells in vivo. Our three specific aims will use cutting-edge technology, most of which has been developed by our laboratory during the previous funding cycle, to examine the priming, effector function and survival, of Salmonella-specific CD4 T cells throughout the course of Salmonella infection.

Public Health Relevance

Typhoid is a potentially fatal disease caused by oral Salmonella infection and recognized as a potential bioterrorist threat in the US. This proposal will examine the protective CD4 T cell response to this organism using a mouse model of Salmonella infection and newly developed immunological tools to detect mucosal and systemic responses. This proposal will therefore increase our understanding of how these protective CD4 T cells are activated and function in the face of mucosal bacterial infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
Program Officer
Alexander, William A
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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