Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening systemic disease that is responsible for significant morbidity and mortality annually worldwide. Approximately 3-5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the site of persistence. S. Typhi is a human-restricted pathogen, therefore asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that gallstones aid in the development and maintenance of GB carriage in a mouse model and in humans, serving as a substrate to which salmonellae attach and form a protective biofilm. However, the molecular basis of chronic carriage of Salmonella in the GB, both from the host and bacterial perspectives, is poorly understood. Our goal is to better understand the environment that allows for asymptomatic chronic carriage and to develop therapies to reverse/prevent it.
In Aim 1 of this proposal, we will examine the ongoing dynamics of the GB response to Salmonella colonization in our gallstone mouse model to better understand the role of the host in permitting asymptomatic chronic carriage. We will also expand preliminary data implicating IL-10 in the development of GB chronic colonization.
In Aim 2, we intend to examine the response and adaptation of the bacterium throughout the establishment of chronic infection, including genes specifically expressed in carriers and putative GB-driven adaptive mutations, in enhancing biofilm formation and colonization.
In Aim 3, we will initiate development of novel treatments for chronic carriage that have emerged from our discovery research efforts. These approaches target kinases required for biofilm formation and the gallstone itself. This work will identify key host and bacterial factors at play during chronic infection of the GB by Salmonella, thus presenting new targets for therapeutic/preventive approaches to eliminate the carrier state.
Research proposed in this application will support pioneering studies on the development and treatment of Salmonella gallbladder carriage (aka Typhoid Marys). As we have demonstrated a role for Salmonella biofilm formation on gallstones as a primary mechanism of carriage, we propose to characterize both the host (gallbladder) and bacterial responses that allow carriage to develop and persist. This work will also test novel therapeutic interventions to prevent the development/maintenance of S. Typhi gallbladder carriage.
|González, Juan F; Alberts, Halley; Lee, Joel et al. (2018) Biofilm Formation Protects Salmonella from the Antibiotic Ciprofloxacin In Vitro and In Vivo in the Mouse Model of chronic Carriage. Sci Rep 8:222|
|Eade, Colleen R; Hung, Chien-Che; Bullard, Brian et al. (2016) Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD. Infect Immun 84:2198-2208|
|Adcox, Haley E; Vasicek, Erin M; Dwivedi, Varun et al. (2016) Salmonella Extracellular Matrix Components Influence Biofilm Formation and Gallbladder Colonization. Infect Immun 84:3243-3251|
|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|
|Gonzalez-Escobedo, Geoffrey; Gunn, John S (2015) In vitro modeling of gallbladder-associated Salmonella spp. colonization. Methods Mol Biol 1225:227-35|
|Eguale, Tadesse; Gebreyes, Wondwossen A; Asrat, Daniel et al. (2015) Non-typhoidal Salmonella serotypes, antimicrobial resistance and co-infection with parasites among patients with diarrhea and other gastrointestinal complaints in Addis Ababa, Ethiopia. BMC Infect Dis 15:497|
|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|
|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|
|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|