Salmonella enterica serovar Typhi (S. Typhi) is an intracellular pathogen and the causative agent of Typhoid. S. Typhi is transmitted via oral-fecal route, commonly through contaminated food or water, and is endemic in developing countries that lack adequate sanitation systems. In addition to systemic disease, it has been demonstrated that Salmonella infections result in anemia as well as the disruption of erythroid development in a manner that is not well understood. Several vaccines have been developed against Salmonella; however, these vaccines have been shown not to confer full protection and are only effective for roughly a two-year period, demonstrating that current vaccine strategies require revision. Systemic Salmonella infections are commonly treated with antibiotics; however, it has been demonstrated that doing so causes relapsing infection and confers no lasting protection in antibiotic-treated individuals, suggesting that rapid bacterial clearance hinders the development of adaptive immunity. It is well appreciated that CD4 T cells are required for protection to Salmonella, however, the lack of protection to secondary infection demonstrates an imperfect understanding. Collectively, the above represent a fundamental lack of understanding in the field with regard to requirements for effective memory formation to systemic Salmonella infections.
Development of mature erythrocytes from hematopoietic stem cells requires erythropoietin, a process which has been shown to be interrupted in Salmonella infections. To examine why this occurs, we developed a model of systemic infection in mice lacking the erythropoietin receptor. When compared to wild-type mice that were similarly infected, it became apparent that Salmonella induced splenomegaly, due to an increase in erythropoietin from kidneys and liver, resulting in a large number of immature erythrocytes. These data may then suggest a duality of host-pathogen interaction whereby the host immune system may be working to sequester iron away from the pathogen while the pathogen is attempting to drive production of iron for its own growth benefits. Future studies should focus then on clearly delineating the role of host, as well as pathogen, in this process and how it may be modulated to reduce bacterial burden in the host while preventing anemia.
To examine the requirements for full protection to systemic Salmonellosis, we developed a mouse model whereby live-attenuated Salmonella was administered systemically and then utilized antigen specific reagents to track Salmonella-specific CD4 T cell memory formation. Antigen-specific CD4 T cells were present in both the peripheral blood as well as in lymphoid and non-lymphoid tissues. We further demonstrate that antigen-specific cells present in the tissue were non-transferable and are indeed required for full secondary protection to virulent Salmonella. Interestingly, vaccination with Salmonella proteins resulted in protection that was mediated via circulating cells and not via tissue-resident cells, however this protection does eventually fail. These data then suggest that current vaccine strategies are flawed and require development of tissue-resident cells within the host to be effective and confer lasting protection.
Additionally, we sought to examine why early antibiotic intervention during a primary infection resulted in poor secondary protection. Upon delivering antibiotics shortly after a primary systemic infection, we identified that Salmonella-specific CD4 T cells were in a lower abundance in both peripheral blood as well as in tissues compared to mice that resolved the infection naturally. Further, we demonstrate in mice that received antibiotics, fewer terminal effector antigen-specific cells found within the peripheral blood, demonstrating a skewed phenotype. Taken together, these data suggest that the expansion of antigen-specific cells and seeding of tissue does not occur due to the rapid clearance of Salmonella from the host. Future studies should therefore focus on the ability to deliver antibiotics and an additional factor to stimulate the development of antigen-specific memory CD4 T cell while still removing the pathogen from the host.
|Advisor:||McSorley, Stephen J.|
|Commitee:||Bäumler, Andreas, Reardon, Colin|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 79/08(E), Dissertation Abstracts International|
|Keywords:||Antibiotic, Cd4, Host-microbe interaction, Salmonella, T cell memory, Vaccine|
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