Experimental Chagas disease

Abstract

The main focus of this thesis was to develop and utilise experimental models using the protozoan parasite Trypanosoma cruzi. We were especially interested in studying the activation of NK cells early after T. cruzi infection and what factors that predispose to a chronic inflammatory disease after T. cruzi infection.

NK cells have previously been demonstrated to play a protective role early during T. cruzi infection. Here we define a model system that allows further characterisation of the activation of NK cells by describing kinetics of the induction of increased NK cell-mediated cytotoxicity and the production of IFN-gamma after T cruzi infection. NK cell-mediated cytotoxicity was increased during the whole first week post-infection and this increase was initially dependent on IFN-alpha/beta. NK cell dependent, IL- 12/IL-23-independent IFN-gamma was transiently produced at 24 hours post-infection. Later during the first week IFN-gamma was once again produced, but now by CD4+ T cells in an IL-12/IL-23-dependent/NK cell-independent manner. IL-12/IL-23 but not IFN-alpha/beta was necessary for survival, suggesting that NK cell-dependent cytotoxicity does not play a protective role during T. cruzi infection.

In order to study what factors are involved in the induction of a chronic inflammatory disease after T cruzi infection we continued the characterisation of an experimental model of Chagas' disease previously established in our lab. We found that CBA/J mice infected with the Tulahuen strain of T. cruzi developed polymyositis, thus enabling the study of idiotypic inflammatory myopathies, a spectrum of diseases almost completely lacking appropriate model systems. To improve the models we have at hand for studying Chagas' disease we then went on to study the relative contribution of host and parasite genotypes, respectively. By combining different host and parasite genotypes through experimental infections we demonstrated that host genotypes could determine whether the final outcome is inflammatory disease or healing whereas parasite genotype at least can determine the phenotype as well as the severity of the inflammatory disease.

Finally we investigated the role of Toll-like receptors in experimental Chagas disease. Utilising a previously established model we demonstrated that signalling through the Toll-like receptor adaptor protein MyD88 is not needed for a protective immune response to T cruzi. Mice deficient of MyD88 did exhibit a less severe chronic inflammatory disease in skeletal muscles, however, suggesting that signalling by Toll-like receptors or IL- 1/IL- 18 plays a role in experimental Chagas' disease.