The Role of Macrophages in Immune Responses to Giardia

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Abstract Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide, often resulting in nutrient malabsorption which can lead to physical and cognitive developmental defects in children. Paradoxically, recent data also indicate that the presence of Giardia is associated with reduced levels of moderate-to-severe diarrhea in children. The infection is transmitted by ingestion of cysts and the cyst wall contains large amounts of N-acetyl galactosamine (GalNAc) polymer. The macrophage galactose-binding lectin (MGL) is the dominant lectin capable of recognizing GalNAc. Our hypothesis is that recognition of cyst wall material by MGL plays a significant role in determining the outcome of infections by modulating both innate and adaptive immune responses. Specifically, we hypothesize that stimulation of macrophages through MGL1 potentiates the production of IL-10 in response to other activating signals such as the presence of bacteria. This IL-10 may enhance parasite persistence, but also limits pathology and decreases disease severity. We will address these hypotheses utilizing in vitro cultures of macrophages derived from MGL1 deficient mice. We will also analyze infections with Giardia, alone and in combination with another parasite known to induce severe inflammatory pathology in mice, using mice deficient in MGL1 as well as mice lacking macrophages. We will assay the parasite burdens and markers of pathology during infections. Bone marrow chimeras will be used to identify roles of MGL1 on specific cell types.