A new mouse model of typhoid fever using Salmonella enterica serovar Paratyphi C as a surrogate pathogen

Salmonella enterica serovar (S.) Typhi, the etiological agent of typhoid fever, is strictly human adapted, which presents a significant challenge for studying its pathogenesis in animal models. A common strategy to overcome this limitation is to infect mice with S. Typhimurium as a surrogate pathogen. Since S. Typhimurium is a non-typhoidal serovar that does not encode the virulence-associated capsular polysaccharide (Vi antigen) of S. Typhi, we explored whether the mouse virulent typhoidal Salmonella serovar Paratyphi C, which expresses the Vi antigen, would be better suited as a surrogate pathogen to study typhoid fever pathogenesis in the mouse. In contrast to the nontyphoidal serovar Typhimurium, which produced lethal morbidity in C57BL/6 mice within a few days after infection, S. Paratyphi C demonstrated prolonged colonization of systemic organs for up to 28 days after infection. Analysis of virulence factors revealed that the Vi antigen was important at very early stages after infection (up to 2 days), whereas the type III secretion system encoded by Salmonella pathogenicity island 2 became critical at later stages. Vaccination with purified Vi antigen suppressed S. Paratyphi C dissemination. Implantation of a biotelemetry device revealed that S. Paratyphi C triggered fever after an incubation period of 3 days, which was reminiscent of the prolonged incubation period of typhoid fever. In conclusion, our findings suggest that the use of S. Paratyphi C as a surrogate pathogen provides a mouse model for studying typhoid fever pathogenesis and vaccine development.IMPORTANCEThe emergence of extensively drug-resistant Salmonella enterica serovar (S.) Typhi poses a serious threat to public health, but its host restriction to humans poses a challenge for studying pathogenesis and vaccine development in animal models. Here, we used S. Paratyphi C, a mouse virulent typhoidal serovar that expresses the virulence-associated Vi capsular polysaccharide, as a surrogate pathogen for studying typhoid fever in a mouse model. Our model recapitulates key features of typhoid fever, including clinical symptoms such as a prolonged incubation period, fever, and splenomegaly. Notably, disseminated infection with S. Paratyphi C developed after inoculation by the natural oral route. We demonstrate the utility of this model for studying pathogenesis and vaccination. We conclude that our new mouse model for typhoid fever offers a promising platform for evaluating novel therapeutics and vaccine candidates to address the problem of drug resistance in S. Typhi and reduce the global burden of typhoid fever.