Abstract
New therapeutic approaches for gastrointestinal inflammatory disorders are sorely needed. Children infected with the protozoan parasite Giardia duodenalis exhibit attenuated gut inflammatory responses via unknown mechanisms. The Giardia genome contains 9 cathepsin B (catB) proteases with anti‐inflammatory potential. Objectives. Using complimentary models of human intestinal biopsies, mice, and human enterocytes in vitro, to determine if Giardia infections attenuate Clostridium difficile toxin‐induced colitis, and if Giardia trophozoites attenuate interleukin‐8 (CXCL8) secretion from intestinal epithelial cells. Results. Reduced neutrophil (PMN) recruitment was observed in Giardia‐infected mice following rectal administration of C. difficile toxins. Co‐incubation of Giardia trophozoites with human small intestinal mucosal biopsy tissues ex vivo, or in vitro Caco‐2 monolayers resulted in attenuated of IL‐1β‐ or Salmonella‐induced CXCL8 secretion via catB‐mediated degradation of CXCL8. Giardia catB proteases also attenuated CXCL8‐induced PMN chemotaxis. Conclusion. Giardia trophozoites secrete catB proteases that degrade CXCL8 and attenuate CXCL8‐induced PMN chemotaxis. Parasitic protease‐mediated reduction of PMN’s may offer a promising therapeutic avenue for intestinal inflammatory disorders. Funding provided by NSERC, AIHS, and CCFC.
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