Leaky Gut Mechanisms in Giardiasis

Giardia duodenalis is a common intestinal pathogen transmitted via consumption of contaminated water. In addition to causing intestinal distress symptoms, Giardia infection is one of the top 5 infectious causes of growth stunting in children under two. Growth faltering is a complex pathology facilitated by changes in the intestinal barrier and enzymatic deficiencies. While infection is widely associated with barrier damage in vitro, in animal models, and in patient studies, the mechanisms behind this process are not well understood. Since PAR2 has a prominent role in increased intestinal permeability in Celiac disease, we are focusing on the involvement of the protease activated receptor 2 (PAR2) in giardiasis-facilitated intestinal defects. We are using human intestinal cell lines, murine intestinal organoids, and a mouse infection model to address the role of PAR2. Co-culture of Giardia and Caco2 cells results in altered tight junction morphology as revealed by staining for ZO-1; these changes are reduced by treatment with a PAR2 antagonist. Effects of PAR2 signaling on barrier function are being assessed by measuring transepithelial electrical resistance (TEER) in Caco2 cells and PAR2+/− and PAR2−/− organoids cultured on transwell filters. Additionally, while C57BL/6 mice fed a low-protein diet exhibit reduced weight gain when infected with Giardia, mice lacking PAR2 gain weight normally when infected. These data indicate that PAR2 signaling contributes to intestinal permeability defects and growth faltering. Identifying parasite factors that activate PAR2 will provide novel targets for development of pharmaceuticals and vaccines to improve child growth. AI166467