In vivo success of Trypanosoma cruzi is regulated by host cell type and parasite sensing of host cell health
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The protozoan parasite Trypanosoma cruzi establishes persistent infections in mammals and causes Chagas disease in humans. In mammals, T. cruzi trypomastigotes invade host cells and proliferate within as amastigotes. In order to reduce progression and improve control of T. cruzi infection, I aim to firstly understand and manipulate host macrophage invasion by T. cruzi, and secondly block amastigote-to-trypomastigote differentiation (trypomastigogenesis). One of the molecules that impacts the interaction of T. cruzi and macrophages is T. cruzi calreticulin (CalR). Here I show that the over-expression of CalR increased T. cruzi: macrophage interactions, impacting both the host and immune effector roles of macrophages by enhancing the initial infection and parasite expansion followed by accelerated reduction of parasite burden. The increased invasion in phagocytes upon CalR overexpression was mediated largely via recognition of surface and secreted T. cruzi CalR by low-density lipoprotein receptor-related protein 1 (LRP1), an endocytic receptor primarily expressed on phagocytes. Thus enhancing the interaction of T. cruzi with macrophages may exert a complex effect on the infection, initially potentiating parasite growth in permissive, non-activated macrophages but decreasing parasite success once IFN production activates these phagocytes. Following the proliferation of T. cruzi within host cells, the amastigotes must convert back into trypomastigotes in order to exit the host cell. A previously uncharacterized, kinetoplastid-specific protein (Hyp1) which localizes to the flagellar membrane was shown to be essential for trypomastigogenesis. Disruption of Hyp1 expression completely blocked trypomastigogenesis in vitro and prevented the persistence of T. cruzi in vivo. Hyp1 overexpression in T. cruzi also impaired host cell invasion, further demonstrating the necessity of tightly regulating Hyp1 levels. These findings demonstrate that T. cruzi infection progression in vivo is regulated by the host cell type and conversion of the parasites before exiting the host cell.