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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055743-12
Application #
8432859
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Alexander, William A
Project Start
2003-07-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$354,699
Indirect Cost
$124,375
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Atif, Shaikh M; Lee, Seung-Joo; Li, Lin-Xi et al. (2015) Rapid CD4+ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9. Eur J Immunol 45:513-24
Nanton, Minelva R; Lee, Seung-Joo; Atif, Shaikh M et al. (2015) Direct visualization of endogenous Salmonella-specific B cells reveals a marked delay in clonal expansion and germinal center development. Eur J Immunol 45:428-41
O'Donnell, Hope; Pham, Oanh H; Li, Lin-xi et al. (2014) Toll-like receptor and inflammasome signals converge to amplify the innate bactericidal capacity of T helper 1 cells. Immunity 40:213-24
McSorley, Stephen J (2014) Immunity to intestinal pathogens: lessons learned from Salmonella. Immunol Rev 260:168-82
Atif, S M; Uematsu, S; Akira, S et al. (2014) CD103-CD11b+ dendritic cells regulate the sensitivity of CD4 T-cell responses to bacterial flagellin. Mucosal Immunol 7:68-77
Atif, Shaikh M; Winter, Sebastian E; Winter, Maria G et al. (2014) Salmonella enterica serovar Typhi impairs CD4 T cell responses by reducing antigen availability. Infect Immun 82:2247-54
Li, Lin-Xi; McSorley, Stephen J (2013) B cells enhance antigen-specific CD4 T cell priming and prevent bacteria dissemination following Chlamydia muridarum genital tract infection. PLoS Pathog 9:e1003707
Lee, Seung-Joo; Liang, Li; Juarez, Silvia et al. (2012) Identification of a common immune signature in murine and human systemic Salmonellosis. Proc Natl Acad Sci U S A 109:4998-5003
Lee, Seung-Joo; McLachlan, James B; Kurtz, Jonathan R et al. (2012) Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog 8:e1002499
Griffin, Amanda J; McSorley, Stephen J (2011) Generation of Salmonella-specific Th1 cells requires sustained antigen stimulation. Vaccine 29:2697-704

Showing the most recent 10 out of 28 publications