Target identification for prevention and therapy of "Salmonella" infections

Abstract

In this thesis we investigated maintenance requirements of Salmonella during chronic infections, and determined the relevant antigen properties that might facilitate the development of Salmonella vaccines. Overall, we wanted to achieve two goals: a)To identify suitable targets to eradicate persisting Salmonella. b)Identify antigen properties for developing enteric fever vaccine. To achieve the first goal we established a practical Salmonella mouse infection model for identifying bacterial maintenance functions essential for persistency.Using this model, we evaluated twelve Salmonella defects. Our data revealed extremely relaxed environment of Salmonella during persistency compared to the acute infection. On the other hand, we identified that unsatuarated/ cyclopropane fatty acid synthesis pathway might contain suitable targets for antimicrobial chemotherapy of chronic infections. To achieve the second goal, we tested thirty seven in vivo expressed antigens for immunogenicity and protectivity in a mouse typhoid fever model. We identified novel Salmonella antigens that conferred partial protection against virulent Salmonella in a typhoid fever model. The identified antigens had high sequence conservation among several Salmonella serovars suggesting that these antigens might be suitable as vaccine candidates against systemic Salmonella infection caused by diverse serovars. Using model antigens expressed in Salmonella and autologous antigens, our data also revealed that surface associated antigens might be promising for inducing both humoral and cellular immunity to Salmonella, as recognition of such antigens might enable uniquely detection and destruction of live Salmonella. This may provide a strategy to discover additional protective antigens for Salmonella and other intracellular pathogens.