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. The infection is transmitted buy 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. Sepcifically, we hypothesize that MGL2 on dendritic cells recongizes parasite glycans leading to release of cytokines that promote production of the cytokine IL-17 by both innate and adaptive lymphocytes. IL-17 has recently been shown to be essential for resolution of Giardia infections. The balance between these competing forces will determine whether infections are resolved rapidly or become chronic. We will address these hypotheses by examining infections in mice lacking cells which express MGL2 or which lack MGL2 itself. We wille examine immune rsponses in vivo and in vitro to both cysts and trophozoites to determine the ability of cyst wall carbohydrates to activate immune cells through MGL2. Finally, bone marrow chimeras will be used to identify specific roles of cytokine production by MGL2+ cells.
Giardia is the most commonly diagnosed protozoan cause of diarrhea in the United States. This proposal seeks to understand how the body's immune system initially recognizes the infecting parasite and determines whether and what kind of immune response to produce. This information is essential for developing vaccines against Giardia, as well as understanding how dysregulation of intestinal immunity leads to syndromes such as celiac, disease, food allergies and Crohn's disease.
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