Salmonella enterica sv. Typhi (S. Typhi) is the etiologic agent of typhoid fever in humans and can cause life-threatening infection in normal hosts. Current typhoid vaccines are only moderately immunogenic and
Salmonella enterica sv. Typhi (S. Typhi) is the etiologic agent of typhoid fever in humans and can cause life-threatening infection in normal hosts. Current typhoid vaccines are only moderately immunogenic and protective. Improvements in vaccine technology have been constrained by the lack of a small animal model. S. Typhi is highly adapted to humans and fails to cause progressive infection in normal mice. S. Typhimurium- murine interactions are used to model S. Typhi-human interactions, but murine typhoid and human typhoid exhibit major differences in both pathogen and host determinants. In the application, we report a breakthrough in the development of a small animal model for the study of human typhoid fever, using NOD-scid IL2rgamma null mice engrafted with CD34+ human hematopoietic stem cells from T-cell depleted umbilical cord blood. In preliminary studies, we have shown that S. Typhi Ty2 can replicate in vivo within engrafted mice following intraperitoneal inoculation to cause lethal infection that recapitulates crucial features of human typhoid. In contrast, S. Typhi is unable to cause productive infection in non-engrafted NOD-scid IL2rgamma null animals or immunocompetent NOD controls. This application describes a pilot project to evaluate this new model and rigorously test the hypothesis that S. Typhi requires human mononuclear cells to replicate in vivo.
The specific aims of the project are: 1.Chacterization of the Humanized Mouse Typhoid Model. The novel model will be characterized using microbiol