Infection with Salmonella typhi can cause a chronic, relatively asymptomatic infection of the human gallbladder. S. typhi carriers are responsible for much of the human-to-human spread of typhoid fever. The gallbladder is the storage site for bile, an antimicrobial substance with detergent-like properties. We have shown that bile affects the expression of a number of Salmonella proteins including those involved in several phenotypes associated with virulence (e.g. epithelial cell invasion, motility, antimicrobial/bile resistance). Therefore, the ability to sense and respond to bile is likely an important attribute of Salmonella necessary to establish a chronic carrier state. In addition, a high correlation exists between human gallbladder abnormalities (especially gallstones) and the development of the Salmonella carrier state. We have previously demonstrated that salmonellae form a biofilm on the surface of human gallstones in vitro, and have characterized numerous microbial factors involved in this process.
In Aim 1, recently identified bile-regulated genes, including those involved in host cell invasion and antimicrobial/bile resistance will be used to uncover unique bile-responsive sensory/regulatory pathways.
In Aim 2, we will further characterize the establishment of gallbladder carriage with the study of microbial factors (extracellular matrix) and gallstone factors that play a role in the unique relationship of salmonellae and gallstones. We will also explore the hypothesis that, in addition to gallstone biofilms, invasion of and biofilm formation on the gallbladder epithelium plays a role in carrier development. Finally, we will test our hypotheses and in vitro studies by examining gallstones, gallbladder tissue and bile from human carriers. The results from Aims 1 and 2 will provide information concerning the interplay of the bacterium with the gallbladder environment (bile and gallstones) on the establishment of this chronic infection. The knowledge gained may suggest therapeutic or preventative approaches to interfere with bile resistance, bile sensing, or biofilm formation, which could eliminate gallstone carriage and dramatically limit the spread of this organism. Public description: Typhoid fever can result in the asymptomatic carriage and shedding of Salmonella. The primary location of carriage is the gallbladder, but little is known about how Salmonella can cause chronic infection of this organ. We hypothesize that bile salts signal phenotypic changes in the bacterium that adapt it to life in the gallbladder, including enhanced colonization/biofilm capabilities and reduced invasiveness. We intend to study bile signaling in Salmonella, as well as the effect of bile on gallstone biofilms and gallbladder epithelial cell invasiveness in vitro. Planned experiments also include those to study our hypotheses in human carriers.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-H (02))
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Alexander, William A
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Ohio State University
Schools of Medicine
United States
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Koopman, Jacob A; Marshall, Joanna M; Bhatiya, Aditi et al. (2015) Inhibition of Salmonella enterica biofilm formation using small-molecule adenosine mimetics. Antimicrob Agents Chemother 59:76-84
Marshall, Joanna M; Gunn, John S (2015) The O-Antigen Capsule of Salmonella enterica Serovar Typhimurium Facilitates Serum Resistance and Surface Expression of FliC. Infect Immun 83:3946-59
Marshall, Joanna M; Flechtner, Alan D; La Perle, Krista M et al. (2014) Visualization of extracellular matrix components within sectioned Salmonella biofilms on the surface of human gallstones. PLoS One 9:e89243
Gunn, John S; Marshall, Joanna M; Baker, Stephen et al. (2014) Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol 22:648-55
Eguale, Tadesse; Marshall, Joanna; Molla, Bayleyegn et al. (2014) Association of multicellular behaviour and drug resistance in Salmonella enterica serovars isolated from animals and humans in Ethiopia. J Appl Microbiol 117:961-971
Gonzalez-Escobedo, Geoffrey; La Perle, Krista M D; Gunn, John S (2013) Histopathological analysis of Salmonella chronic carriage in the mouse hepatopancreatobiliary system. PLoS One 8:e84058
Gonzalez-Escobedo, Geoffrey; Gunn, John S (2013) Identification of Salmonella enterica serovar Typhimurium genes regulated during biofilm formation on cholesterol gallstone surfaces. Infect Immun 81:3770-80
Gonzalez-Escobedo, Geoffrey; Gunn, John S (2013) Gallbladder epithelium as a niche for chronic Salmonella carriage. Infect Immun 81:2920-30
Gonzalez-Escobedo, Geoffrey; Marshall, Joanna M; Gunn, John S (2011) Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol 9:9-14
Crawford, Robert W; Reeve, Kristin E; Gunn, John S (2010) Flagellated but not hyperfimbriated Salmonella enterica serovar Typhimurium attaches to and forms biofilms on cholesterol-coated surfaces. J Bacteriol 192:2981-90

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