Browsing by Author "Cotton, James"

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    Epithelial Immunomodulation by Giardia
    (2015-09-25) Cotton, James; Buret, Andre
    Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a non-invasive, protozoan parasite of the upper small intestine of animals, including humans. Despite parasite loads exceeding 106 trophozoites per cm of small intestine, the intestinal mucosa in the majority of the Giardia-infected individuals are devoid of signs of overt inflammation. Human studies also suggest Giardia infections are capable of modulating the development of diarrheal disease in their host via unknown mechanisms. The first part of this study focused on whether Giardia infections were capable of attenuating neutrophil (PMN) accumulation in different experimental models of inflammation. Accumulation of PMNs is an archetypal event during many acute intestinal inflammatory responses contributing to the development of diarrheal disease. Our findings demonstrated Giardia infections attenuate granulocyte infiltration in an experimental model of colitis, in an isolate-dependent manner. Giardia infections also decrease tissue expression of mediators associated with PMN recruitment during in vivo colitis. Similar results were observed when Giardia trophozoites were incubated ex vivo with inflamed mucosal biopsy tissues collected from the descending colon of patients with Crohn’s disease. The second part of this study focused on identifying mechanisms by which Giardia trophozoites attenuate PMN accumulation. The intestinal epithelium is a single layer of polarized cells separating the external environment from underlying host tissues. In response to pro-inflammatory stimuli, this structure releases the PMN chemokine interleukin-8 (CXCL8) that recruits PMNs to the basolateral membrane of the intestinal epithelium. We demonstrated that Giardia trophozoites attenuate CXCL8 secretion from ex vivo small intestinal mucosal biopsy tissues and in vitro Caco-2 monolayers, following administration of IL-1β or Salmonella sp.; this involved parasite-mediated degradation of CXCL8 and attenuation of CXCL8- and C5a-induced PMN chemotaxis. Genetic assemblages of Giardia capable of infecting humans contain unique cathepsin proteases and Giardia trophozoties release cathepsin proteases into supernatants. Inhibition of Giardia cathepsin B proteases prevented parasite-mediated degradation of CXCL8 and attenuation of CXCL8 and C5a-induced PMN chemotaxis. Our findings demonstrate that Giardia infections attenuate PMN accumulation in an in vivo model of colitis. Research done in vitro highlights a role for Giardia cathepsin B proteases in degrading CXCL8 and attenuating CXCL8-induced PMN chemotaxis.