Bobat, Saeeda (2011)
Ph.D. thesis, University of Birmingham.
Immunity to Salmonella enterica serovar Typhimurium (STm) is complex and requires both cell mediated and humoral immunity at different stages of infection. In infants in sub-Saharan Africa infection with non-typhoidal Salmonella (NTS), such as STm, can commonly cause fatal invasive disease. Evidence indicates that disease may be preventable by antibody, which makes vaccine development against these devastating infections a promising option. This work has explored the cell-mediated and humoral response to STm and its component antigens, their intrinsic properties, and capacity to act as protective immunogens in a mouse model. In particular, responses to surface exposed structures such as the outer membrane proteins (Omps) and the flagellar protein FliC, which are potent, immunodominant antigens and frequent targets of antibody, that may offer potential as vaccine candidates have been examined. Immunisation with soluble flagellin (sFliC) induces a potent Th2 response. Despite this, immunisation with sFliC results in accelerated clearance of STm after the first week of infection in an antibody independent, but T-bet-regulated manner. This suggests that the Th2 responses to flagellin are flexible since they can promote Th1 mediated clearance of STm. This moderate protection conferred by sFliC contrasts with the potent benefit conferred by porins. These proteins induce, and can mediate protection through a T-independent B1b cell population. In particular, antibody to OmpD is key for this protection. These results suggest that vaccines that induce protective antibody to STm may be more effective than vaccines that induce T cell-mediated protection, since they reduce bacterial numbers at the earliest stages of infection. Lastly, experiments using N. brasiliensis show that infectious history can impact on the host’s ability to control primary STm infection and the efficacy of antibody-mediated protection against infection. These projects further our understanding of the relationship between host and pathogen and the mechanisms used to control infection, but also identify the need to consider the impact of infectious history on the host’s capacity to implement protective immunity.
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