A collaborative cross mouse model of Salmonella Typhi Chronic Carriage

Salmonellae are Enterobacteriaceae that cause a spectrum of disease in humans and animals including enteric(typhoid) fever and gastroenteritis. Typhoid fever caused primarily by Salmonella enterica serovar Typhi (S.Typhi) results in a life-threatening systemic disease that is responsible for significant morbidity and mortalityworldwide. Approximately 5% of individuals infected with S. Typhi become chronic carriers with the gallbladder(GB) as the site of persistence and these asymptomatic carriers represent a critical reservoir for further spreadof disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriagein a mouse model (utilizing S. Typhimurium which causes a typhoid-fever like disease in mice) and in humansserving as a substrate to which salmonellae attach and form a protective biofilm. Thus biofilm formation is a keystep in the establishment of carriers. Until recently typhoid fever has lacked a direct in vivo model as S. Typhiis host-restricted to humans. Recently the Collaborative Cross project has produced a mouse strain (CC003)that is permissive to S. Typhi infection which we have utilized to create a model of chronic S. Typhi infection.This model will be more physiologically relevant to human disease as it will utilize the causative infectious agentand not a closely related serovar. We hypothesize that the CC003 mice are permissive to S. Typhi chronicinfection through biofilm formation on gallstones and immune suppression. Further we hypothesize that treatingchronically infected mice with our lead anti-biofilm agents will clear the carrier state. In Aim 1 we will determinewhether S. Typhi chronic infection is mediated by biofilm formation on cholesterol GSs and characterize theinflammatory response within the GB of infected mice. Studies in Aim 2 will determine whether anti-biofilmcompounds in combination with antibiotics can clear the chronic carrier state of S. Typhi in the CC003 mousemodel. These experiments will develop a more physiologically relevant model of chronic typhoid fever andcharacterize potential therapeutics.