NMR Studies Of The Effects Of Attenuated Salmonella Typhimurium On The Schistosoma Japonicum Infected Mice’s Metabolome

Schistosomiasis is a worldwide parasitic zoonosis, which is always accompanied with pyrexia, emaciation, anemia and even death. So, the development of an safe and effective vaccine has become a hot issue in the anti-schistosomiasis researches, which is likely to be the fundamental way to prevent and control schistosomiasis in future. Salmonella typhimurium belongs to the intracellular, invasive, facultative anaerobic bacteria. The safety of attenuated salmonella typhimurium is greatly improved, and it has already been used in the vaccine development of viruses, bacteria, and parasites. However, there is no research using metabonomic approach to systematically study the metabolic changes in the mice after oral delivery of attenuated Salmonella typhimurium, and little is known about changes and characteristics of the metabolites under the combined action of attenuated Salmonella typhimurium and Schistosoma japonicum.For these reasons, this thesis employed NMR techniques coupled with multivariate data analysis methods to carry out two aspects of metabonomic studies including the metabolic responses of mice to attenuated Salmonella typhimurium infection and the effects of attenuated Salmonella typhimurium on the metabolome of Schistosoma japonicum infected mice.First, the enzyme linked immunosorbent assay (ELISA) and NMR-based metabonomic approach were used to systematically analyse the immune effects and the metabolic changes in plasma, urine, liver and spleen. ELISA results showed that the plasma levels of IFN-y were markedly elevated in the attenuated Salmonella typhimurium infected mice, which indicated an enhanced Thl-type cellular immune response. In addition, the main metabolic changes were presented with promotion of gluconeogenesis, alteration of amino acids, enhanced β-oxidation of fatty acids, increased synthesis of choline, disturbance of nucleotide metabolism and activation of gut microbiota. The alterations of those metabolites show that attenuated Salmonella typhimurium can cause lasting metabolic responses in mice.Second, in order to explore the effects of attenuated Salmonella typhimurium on Schistosoma japonicum infected mice, which were subcutaneously infected with60Schistosoma japonicum cercariae after oral adminstration of attenuated Salmonella typhimurium. All adult Schistosoma japonicum worms were counted, and the metabolic variations induced by the combined effects of attenuated Salmonella typhimurium and Schistosoma japonicum were observed5weeks after infection. The results showed that the above co-infection could effectively stimulate enhanced immune responses and significantly reduce the worm burden. The metabolic alterations of co-infected mice were represented with accumulation of amino acids, temporary rise of liver glycogen and glucose, promotion of glycolysis, suppression of tricarboxylic acid cycle, inhibition of fatty acid β-oxidation, blocked synthesis of choline, abnormality of nucleotide metabolism and functional disorder of gut microbiota.To sum up, this thesis is helpful to further understand the interaction mechanism between host and multi-pathogen, and it also provides the basic metabolomic data for the development of parasite vaccines, which use attenuated Salmonella typhimurium as a carrier.