The Cysteine Protease Giardipain-1 from Giardia duodenalis Contributes to the Disruption of Intestinal Homeostasis in Experimenal Giardiasis. jirds metagenome

Infection with Giardia duodenalis can cause diarrhoea, dehydration, malabsorption and/or weight lost, indicating epithelial barrier disturbance by the parasite. However, the pathophysiological mechanisms or processes leading to intestinal epithelial barrier dysfunction during giardiasis are not yet fully understood. Here, we present evidence that giardipain-1, a cysteine protease of Giardia duodenalis, directly contributes to the pathogenesis of giardiasis. We demonstrate using an ex vivo intestinal loop model that purified giardipain-1 induces apoptosis and extrusion of epithelial cells at the tips of the villi in infected jirds (Meriones unguiculatus) and that trophozoites expressing giardipain-1 damaged the intestinal epithelium which associated with cellular infiltration, crypt hyperplasia, goblet cell hypertrophy and edema. Pathological alterations were more pronounced in jirds infected intragastrically with Giardia trophozoites that stably overexpress giardipain-1 than those observed in the loop model. Furthermore, we show that Giardia colonization in jirds results in a chronic inflammation that could relate to the dysbiosis triggered by the protist. Taken together, these results reveal that giardipain-1 plays a key role in the pathogenesis of giardiasis.