Microbial pathogens produce proteins that can be recognized by the adaptive immune response in an infected host. Identification of these immune targets is a prerequisite for the rational design of novel vaccines and better diagnostics, including those directed against the category B bioterrorism agent Salmonella.
The specific aims of this proposal are:
Aim 1. Use an established high throughput screening technology to identify common aspects of the Salmonella proteome recognized by antibodies induced by Salmonella infection.
Aim 2. Identify and confirm antigenic targets of Salmonella-specific CD4 T cells from among the targets of isotype-switched antibody responses.
Aim 3. To generate a prototype sub-unit typhoid vaccine that is immunogenic and protective in highly susceptible mouse strains. Our preliminary data demonstrate that high throughput screening of microbial proteomes is an effective strategy for the identification of microbial proteins targeted by the adaptive immune response. Our hypothesis is that identification and production of natural antigenic targets of Salmonella-specific responses will allow the development of improved diagnostics and a sub-unit vaccine for typhoid fever, a disease that kills over 600,000 people per year and is a significant bioterrorism threat to the US. The elderly and very young are most at risk from typhoid, yet currently available live attenuated vaccines are not licensed for use in these populations. There is an urgent need to develop an effective sub-unit vaccine that could be specifically targeted to the most vulnerable demographics. Our hypothesis will be tested using novel high-throughput proteome technology to identify Salmonella protein targets of the adaptive immune system and develop a prototype sub-unit vaccine for typhoid.

Public Health Relevance

Typhoid is an infectious disease that kills over 600,000 people per year in developing countries and has been recognized as a potential bioterrorist threat in the US. This proposal aims to identify the major antigenic targets recognized by antibodies and T cells from infected mice and humans, and use this information to generate a novel sub-unit vaccine. This proposal therefore has the potential to uncover target antigens that may be important in the development of novel vaccines and diagnostics for typhoid fever.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073672-02
Application #
7676808
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Alexander, William A
Project Start
2008-08-20
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$350,005
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Charles, Richelle C; Liang, Li; Khanam, Farhana et al. (2014) Immunoproteomic analysis of antibody in lymphocyte supernatant in patients with typhoid fever in Bangladesh. Clin Vaccine Immunol 21:280-5
Liang, Li; Juarez, Silvia; Nga, Tran Vu Thieu et al. (2013) Immune profiling with a Salmonella Typhi antigen microarray identifies new diagnostic biomarkers of human typhoid. Sci Rep 3:1043
Nanton, Minelva R; Way, Sing Sing; Shlomchik, Mark J et al. (2012) Cutting edge: B cells are essential for protective immunity against Salmonella independent of antibody secretion. J Immunol 189:5503-7
Li, Lin-Xi; Atif, Shaikh M; Schmiel, Shirdi E et al. (2012) Increased susceptibility to Salmonella infection in signal regulatory protein ýý-deficient mice. J Immunol 189:2537-44
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
McGeachy, Mandy J; McSorley, Stephen J (2012) Microbial-induced Th17: superhero or supervillain? J Immunol 189:3285-91
Griffin, Amanda J; McSorley, Stephen J (2011) Generation of Salmonella-specific Th1 cells requires sustained antigen stimulation. Vaccine 29:2697-704
Srinivasan, Aparna; Nanton, Minelva; Griffin, Amanda et al. (2009) Culling of activated CD4 T cells during typhoid is driven by Salmonella virulence genes. J Immunol 182:7838-45

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