Examining immune responses in a mouse model of Salmonella infection

Abstract

Salmonella infections are responsible for significant morbidity and mortality throughout the world. Although extensive research has elucidated the mechanisms of protective immunity following vaccination with live vaccine strains (LVS) of Salmonella, very little work has been done to examine immune responses during and following antibiotic treatment of virulent Salmonella infections. We have developed a murine model of naturally acquired immunity to Salmonella, where susceptible mice are orally infected with virulent S. typhimurium and treated with antibiotics for an extended period of time. These mice demonstrate weak protective immunity to rechallenge with virulent Salmonella, which is due to Th1 and antibody responses and can be augmented by the administration of a TLR5 agonist. We have also used antibiotic treatment to examine the development of Th1 responses to LVS Salmonella, which are vital for mediating protective immunity to this pathogen. We show that Th1 cells develop after sustained exposure to Salmonella antigens. Eradication of the bacteria by antibiotic intervention within one week of primary infection has profound effects on the ability of mice to survive rechallenge with virulent Salmonella. We also establish that full effector/memory function of Th1 cells, as determined by robust production of Th1 cytokines, requires two weeks of exposure to Salmonella antigens. Finally, we use short-term antibiotic treatment to establish a model of relapsing virulent Salmonella infection where mice appear to have cleared the bacteria soon after they begin treatment but suffer recurrent and fatal Salmonella infection upon withdrawal. We demonstrate that Salmonella harbored in CD11b+Gr1- resident monocytes in mouse mesenteric lymph nodes (MLNs) are the source of relapsing infection. In addition, the MLNs appear to act as a filter prohibiting the dissemination of Salmonella to systemic tissues. By using antibiotic treatment to examine immune responses to Salmonella, this thesis work may contribute to future research in the development of efficacious therapeutic and/or preventative typhoid vaccines. Moreover, these studies may stimulate future studies using these same tools in other infectious disease models.