A System to Study Salmonella Typhi Infection and Immunity

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Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Global estimates indicate that 21.6 million cases of typhoid fever occur each year resulting in 226,000 deaths. Although antibiotics are the primary treatment option, the emergence as well as spreading of multidrug-resistant S. Typhi strains is occurring globally at an alarming rate. This is, in fact, currently limiting this treatment option, particularly in disease-endemic countries. Typhoid is a vaccine-preventable disease and vaccination of high-risk populations is considered the most promising strategy for control, although sustained vaccine efficacy has remained elusive. Little is known about the mechanisms governing the pathophysiology of typhoid or the correlates of immunological protection in vaccinated individuals, further complicating efforts to understand vaccine-mediated protection. One of the greatest barriers to advancing the treatment and prevention of typhoid is the lack of a suitable experimental animal model to study S. Typhi infection. S. Typhi is regarded as a human-restricted pathogen and does not productively infect commonly used inbred laboratory mice. Genetic variation in humans is far greater and more complex than that in commonly used inbred laboratory mice, which may in part provide an explanation for the differences in the infection susceptibility and progression in humans and mice. The Collaborative Cross (CC) is a large panel of recombinant inbred mouse strains that incorporate a wider range of genetic diversity than is present in other inbred mouse strains. To test whether CC strains are permissive to S. Typhi infection, we have infected mice from 6 randomly chosen CC lines, along with 4 of the 8 CC progenitor inbred lines and one non CC progenitor (i.e. BALB/c), with the well-characterized S. Typhi strain Ty2. We found that unlike commonly-used laboratory mice, such as BALB/c, C57BL/6 or 129S1/Sv, two of the CC strains, CC003/Unc and CC053/Unc, showed bacterial burdens several orders of magnitude higher in the spleen relative to the actual number of bacteria injected during infection, demonstrating survival and replication of S. Typhi in these two CC strains. Analysis of liver histology in these infected CC mice shows lesions that are consistent with the histological features found in liver biopsies of typhoid patients. We also found that the S. Typhi-susceptible CC strains are immune-competent and upon immunization generate protective immune responses that are capable of killing S. Typhi in vitro and controlling S. Typhi in vivo. The proposed work in this R21 application will permit us to explore novel prophylactic and therapeutic interventions approaches for typhoid control in humans and gain insights into host genetic factors influencing susceptibility and resistance to S. Typhi infection.