Salmonella typhimurium causes inflammatory diarrhea in immunocompetent individuals, while in immunocompromised patients it causes bacteremia with a high mortality rate. The early inflammatory response elicited by S. typhimurium is beneficial to the host because it confines the infection to the gut mucosa. However, aspects of this response are also beneficial to S. typhimurium as they are exploited to successfully colonize the gut and achieve transmission to the next susceptible host. Very little is known about which mucosal inflammatory responses constitute the mucosal barrier to systemic Salmonella dissemination and which are exploited by Salmonella to colonize the gut. Our long-range goal is to understand how the intestinal mucosal barrier functions as well as how it is altered in individuals at higher risk for systemic infections. The objectives of this application are to investigate the costs and benefits of mucosal inflammation during Salmonella pathogenesis. Our central hypothesis is that a subset of cytokines, namely the TH17 cytokines, orchestrates both the mucosal barrier function that prevents systemic S. typhimurium dissemination and the inflammatory responses that are exploited by S. typhimurium and other bacteria to survive in the inflamed gut. The rationale for the proposed research is that understanding the host-pathogen interaction at the mucosal interface will lead to innovative approaches to treat and prevent infections at mucosal surfaces and to reduce the risk of bacteremia. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aims: 1. Determine which components of the inflammatory response constitute the gut mucosal barrier during S. typhimurium infection. We will investigate the role of IL-17 and IL-22 in orchestrating the mucosal barrier during S. typhimurium infection. 2. Determine the mechanism of induction of lipocalin-2 during S. typhimurium infection. We will investigate the role of IL-17 and IL-22 in inducing expression of the antimicrobial peptide lipocalin-2- in the gut. 3. Determine whether resistance to lipocalin-2 facilitates colonization of the inflamed gut. We will test the hypothesis that acquisition of the iroABCDE iroN locus confers an advantage for colonization of the gut when lipocalin-2 is expressed.

Public Health Relevance

Salmonella typhimurium causes inflammatory diarrhea in immunocompetent individuals, while in immunocompromised patients it causes bacteremia with a high mortality rate. Very little is known about which mucosal inflammatory responses constitute the mucosal barrier to systemic Salmonella dissemination and which are exploited by Salmonella to colonize the gut. Our long-range goal is to understand how the intestinal mucosal barrier functions as well as how it is altered in individuals at higher risk for systemic infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083663-05
Application #
8602806
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2010-01-15
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$329,339
Indirect Cost
$106,589
Name
University of California Irvine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Sassone-Corsi, Martina; Nuccio, Sean-Paul; Liu, Henry et al. (2016) Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540:280-283
Perez-Lopez, Araceli; Behnsen, Judith; Nuccio, Sean-Paul et al. (2016) Mucosal immunity to pathogenic intestinal bacteria. Nat Rev Immunol 16:135-48
Sassone-Corsi, Martina; Raffatellu, Manuela (2015) No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J Immunol 194:4081-7
Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina et al. (2015) Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms. Am J Physiol Gastrointest Liver Physiol 309:G123-31
Behnsen, Judith; Perez-Lopez, Araceli; Nuccio, Sean-Paul et al. (2015) Exploiting host immunity: the Salmonella paradigm. Trends Immunol 36:112-20
Diaz-Ochoa, Vladimir E; Jellbauer, Stefan; Klaus, Suzi et al. (2014) Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis. Front Cell Infect Microbiol 4:2
Limon, Jose J; So, Lomon; Jellbauer, Stefan et al. (2014) mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc Natl Acad Sci U S A 111:E5076-85
Kortman, Guus A M; Raffatellu, Manuela; Swinkels, Dorine W et al. (2014) Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol Rev 38:1202-34

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