Studies of the pathogenesis and immunology of attenuated mutants of Salmonella enterica var. Typhimurium: Lessons for human typhoid fever?
Dunstan SJ., Simmons CP., Wijburg OLC., Uren TK., van Rooijen N., Strugnell RA.
© 1998, Faculty of Medicine, Universitas Indonesia. All rights reserved. Salmonella enterica var. Typhi and Typhimurium cause similar systemic disease in humans and mice respectively. In mice, resistance to S. Typhimurium is largely controlled by a genetic locus which encodes NRAMP-1 (a protein found within the phagosomal compartment of macrophages. The two phenotypic alleles of NRAMP-I). Itys and ltyR, cause mice to vary in sentivity to S. Typhimurium by 10,000-fold. It is not clear whether there are similar structural alleles in human NRAMP-1, but variability in human NRAMP-I transcription has been reported. The immunology of murine typhoid was, until recently, thought to closely parallel that of human typhoid fever hut recent discrepancies in the behaviour of defined S. Typhimurium and S. Typhi mutants in mice and humans respectively, suggest that there may be some, important differences in the host-pathogen relationships. Our interests have been in defining the key properties of S. Typhimurium as a vaccine vector such that similar properties could be engineered into attenuated S. Typhi. We have studied the expression of C fragment, the protective but non-toxic portion of tetanus toxin, and examined the capacity of different S. Typhimurium mutations, replicons and promoters to deliver protective responses. Mutants were analysed for penetration into central organs eg. liver and spleen, after oral administration, and for their capacity to elicit Salmonellae and tetanus toxoid-specific T and B cell responses. There was a good correlation behveen entry into, and persistence within, the Peyer’s patches and antibody levels, hut no correlation between antibody responses and splenic invasion. There was a positive correlation between splenic T cell responses and splenic invasion. Studies into the role of macrophages and the induction of protection against Salmonellae challenge were also conducted in mice, as part of a larger program to define the cells responsible for inducing and effecting immunity in murine typhoid. Mice were depleted of macrophages prior to immunisation and/or prior to challenge using the Cl2MDP-macrophage depletion techique. Mice depleted of macrophages prior to and during immunisation with S. Typhimurium aroA/aroD (ie. BRD509) expressing C fragment were highly protected against challenge with S. Typhimurim SL 1344; this protection was reduced when macrophages were removed prior to challenge. Macrophage depletion did not reduce antibody responses against tetanus toxoid but, paradoxically, macrophage depletion increased T cell responses specific for C fragment. This results suggest that macrophages are not the primary antigen presenting cell (APC) involved in immunity elicited by BRD509. However, macrophages appear to be important effectors in protection againts virulent S Typhimurium challenge infection. The results from these studies indicate that Salmonella entry into macrophages is not essential for homologous or heterologous responses elicited by mutants of S. Typhimurium and that much of the inductive processes with respect to immunity against virulent Salmonellae, and the heterologous antigens they are engineered to express, may occur in the Peyer’s patch. Clearly, the relation between Salmonellae and host cells within the Peyer’s patch should be explored further in the murine model and attempts should be made to define the S. Typhi-macrophage relationship in humans.