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 mortality worldwide. 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 spread of disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model (utilizing S. Typhimurium, which causes a typhoid-fever like disease in mice) and in humans, serving as a substrate to which salmonellae attach and form a protective biofilm. Thus, biofilm formation is a key step in the establishment of carriers. Until recently, typhoid fever has lacked a direct in vivo model, as S. Typhi is 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 agent and not a closely related serovar. We hypothesize that the CC003 mice are permissive to S. Typhi chronic infection through biofilm formation on gallstones and immune suppression. Further, we hypothesize that treating chronically infected mice with our lead anti-biofilm agents will clear the carrier state. In Aim 1, we will determine whether S. Typhi chronic infection is mediated by biofilm formation on cholesterol GSs and characterize the inflammatory response within the GB of infected mice. Studies in Aim 2 will determine whether anti-biofilm compounds in combination with antibiotics can clear the chronic carrier state of S. Typhi in the CC003 mouse model. These experiments will develop a more physiologically relevant model of chronic typhoid fever and characterize potential therapeutics. Project Number: 1R21AI193287-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: JOHN GUNN | Institution: RESEARCH INST NATIONWIDE CHILDREN'S HOSP, COLUMBUS, OH | Award Amount: $402,985 | Activity Code: R21 | Study Section: Bacterial-Host Interactions Study Section [BHI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19328701