Non-typhoidal Salmonella serotypes are a leading cause of food-borne infections worldwide, with Salmonella enterica serotypes Typhimurium and Enteritidis being isolated most frequently. In immunocompetent individuals, non-typhoidal Salmonella serotypes cause a localized gastroenteritis with low mortality rates. However, non-typhoidal Salmonella serotypes cause a life-threatening bacteremia in immunocompromised patients. The precise immune mechanisms that enable an immunocompetent host to prevent bacterial dissemination and bacteremia are poorly understood. Our long-range goal is to understand the pathogenesis of S. typhimurium infections in immunocompromised patients. The objectives of this application are to investigate the importance of the IL-22/IL-17 axes in preventing S. typhimurium dissemination. Our central hypothesis is that the cytokines IL-17 and IL-22 orchestrate an intestinal epithelial response that aids in containing S. typhimurium at its site of entry, the intestinal mucosa. We plan to test our hypothesis and fulfill the objectives of this application by establishing an animal model for functional studies on the intestinal barrier to S. typhimurium infection and by characterizing epithelial responses orchestrated by IL-17 and IL-22 in vitro and in vivo. The proposed work is innovative because it establishes new model systems and new theoretical concepts for studying the development of bacteremia in immunocompromised patients. It is our expectation that the outcome of the proposed studies will identify the IL-17/IL-22-axes as an arm of the mucosal response that plays a key role in limiting bacterial dissemination from the intestine. This outcome will be significant, because it will identify novel targets for therapeutic intervention in immunocompromised patients.

Public Health Relevance

While non-typhoidal Salmonella serotypes cause a localized gastroenteritis in immunocompetent patients, immunocompromised individuals develop a life-threatening bacteremia. Bacteremia with non-typhoidal Salmonella serotypes is currently a leading cause of hospital admissions and a leading cause of death in Sub-Saharan Africa. Due to the absence of animal models to study Salmonella bacteremia in immunocompromised individuals, our understanding of defects in mucosal barrier function that are responsible for bacterial dissemination is still incomplete. Research proposed in this application will support the pioneering studies needed to establish the models and concepts needed to fill this gap in knowledge. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI079173-01
Application #
7508617
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Alexander, William A
Project Start
2008-06-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$228,000
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Santos, R L; Almeida, A P; Xavier, M N et al. (2011) Enteric pathology and Salmonella-induced cell death in healthy and SIV-infected rhesus macaques. Vet Pathol 48:933-41
Winter, Sebastian E; Baumler, Andreas J (2011) A breathtaking feat: to compete with the gut microbiota, Salmonella drives its host to provide a respiratory electron acceptor. Gut Microbes 2:58-60
Adams, L Garry; Khare, Sangeeta; Lawhon, Sara D et al. (2011) Enhancing the role of veterinary vaccines reducing zoonotic diseases of humans: linking systems biology with vaccine development. Vaccine 29:7197-206
Keestra, A Marijke; Godinez, Ivan; Xavier, Mariana N et al. (2011) Early MyD88-dependent induction of interleukin-17A expression during Salmonella colitis. Infect Immun 79:3131-40
Winter, Sebastian E; Winter, Maria G; Godinez, Ivan et al. (2010) A rapid change in virulence gene expression during the transition from the intestinal lumen into tissue promotes systemic dissemination of Salmonella. PLoS Pathog 6:e1001060
Winter, Sebastian E; Keestra, A Marijke; Tsolis, Renee M et al. (2010) The blessings and curses of intestinal inflammation. Cell Host Microbe 8:36-43
Tran, Quynh T; Gomez, Gabriel; Khare, Sangeeta et al. (2010) The Salmonella enterica serotype Typhi Vi capsular antigen is expressed after the bacterium enters the ileal mucosa. Infect Immun 78:527-35
Tükel, Cagla; Nishimori, Jessalyn H; Wilson, R Paul et al. (2010) Toll-like receptors 1 and 2 cooperatively mediate immune responses to curli, a common amyloid from enterobacterial biofilms. Cell Microbiol 12:1495-505
Chessa, Daniela; Winter, Maria G; Jakomin, Marcello et al. (2009) Salmonella enterica serotype Typhimurium Std fimbriae bind terminal alpha(1,2)fucose residues in the cecal mucosa. Mol Microbiol 71:864-75
Santos, Renato L; Raffatellu, Manuela; Bevins, Charles L et al. (2009) Life in the inflamed intestine, Salmonella style. Trends Microbiol 17:498-506

Showing the most recent 10 out of 19 publications