Investigating the Role of Myeloid Cells in Giardia Immunity

Abstract

Human infections with Giardia duodenalis (giardiasis) is regarded as one of the most common human diarrheal disease worldwide with 280 million cases estimated to occur worldwide each year. This parasite lives a biphasic lifestyle either as a dormant cyst or vegetative trophozoite. Previous work has demonstrated that the cells and mechanisms of the adaptive immune system are critical for clearance of Giardia parasites. However, the innate system has not been as well studied in the context of Giardia infection, including what innate recognition mechanisms the immune system uses to initiate protective or pathologic immune responses during a Giardia infection. This dissertation explores a role for the Mannose Receptor and Macrophage Galactose Lectin receptor in protective immunity and also builds upon past studies that have examined the role of macrophages during Giardia infection. We report a mechanism for macrophage accumulation during Giardia infection that does not correlate with other intestinal diseases in which tissue resident macrophages proliferate in response to infection; however, these resident cells are dispensable for protection. This work also identifies three C-type lectin receptors - MR, MGL1, and MGL2 - that appear to be involved in the signaling of immune responses leading to protection from this parasite. We report that mast cell recruitment appears to be inhibited in MR-deficient mice, suggesting that parasite clearance may be defective due to the loss of mast cells during infection. We also show that MGL2 receptor is required for protective Giardia immunity as depletion of MGL2+ cells lead to a defect in parasite clearance. These cells also may be sources of IL-6, which is known to induce development of Th17 responses. Lastly, our preliminary data suggest that MGL1 found on Macrophages mediate production of IL-10. However, MGL1 engagement must occur with simultaneous co-stimulation by LPS that results in enhanced IL-10 production. This study contributes to a greater understanding of the interaction between Giardia and the immune system. Future studies delving into this host-pathogen interaction is certainly deserved as better therapies and treatments can be developed that can improve the health and well-being of those affected by giardiasis.