Abstract
Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a predominant cause of waterborne diarrheal disease that may lead to post-infectious functional gastrointestinal disorders. Although Giardia-infected individuals could carry as much as 106 trophozoites per centimetre of gut, their intestinal mucosa is devoid of overt signs of inflammation. Recent studies have shown that in endemic countries where bacterial infectious diseases are common, Giardia infections can protect against the development of diarrheal disease and fever. Conversely, separate observations have indicated Giardia infections may enhance the severity of diarrheal disease from a co-infecting pathogen. Polymorphonuclear leukocytes or neutrophils (PMNs) are granulocytic, innate immune cells characteristic of acute intestinal inflammatory responses against bacterial pathogens that contribute to the development of diarrheal disease following recruitment into intestinal tissues. Giardia cathepsin B cysteine proteases have been shown to attenuate PMN chemotaxis towards IL-8/CXCL8, suggesting Giardia targets PMN accumulation. However, the ability of Giardia infections to attenuate PMN accumulation in vivo and how in turn this effect may alter the host inflammatory response in the intestine has yet to be demonstrated. Herein, we report that Giardia infection attenuates granulocyte tissue infiltration induced by intra-rectal instillation of Clostridium difficile toxin A and B in an isolate-dependent manner. This attenuation of granulocyte infiltration into colonic tissues paralled decreased expression of several cytokines associated with the recruitment of PMNs. Giardia trophozoite isolates that attenuated granulocyte infiltration in vivo also decreased protein expression of cytokines released from inflamed mucosal biopsy tissues collected from patients with active Crohn’s disease, including several cytokines associated with PMN recruitment. These results demonstrate for the first time that certain Giardia infections may attenuate PMN accumulation by decreasing the expression of the mediators responsible for their recruitment.
Highlights
Results from the present study demonstrate novel mechanisms through which certain Giardia infections were able to attenuate pro-inflammatory responses elicited by an inflammatory bacterial toxin in vivo, or from inflamed human intestinal tissues ex vivo
Attenuation of granulocyte infiltration in Giardia NF infected animals given TcdAB occurred concomitantly with reduced colonic expression of several inflammatory mediators, including those associated with granulocyte tissue recruitment
Our data suggest that Giardia infections attenuate intestinal pro-inflammatory responses in an isolatedependent manner, and attenuation of such responses is associated with reduced tissue granulocyte infiltration
Summary
As PMN accumulation contributes to the development of diarrheal disease via several different mechanisms [28,42,43,44], we hypothesized that during a Giardia infection, the attenuation of diarrheal disease or the creation of a favourable environment for other co-infecting gastrointestinal pathogens may stem, at least partially, from Giardia’s ability to attenuate PMN recruitment These observations support the notion that Giardia parasites may reduce host inflammatory responses. This study shows that Giardia trophozoites decrease expression of a variety of inflammatory mediators when parasites are co-incubated with inflamed biopsy tissues from patients with Crohn’s disease These results indicate for the first time that certain Giardia isolates are capable of attenuating intestinal inflammatory responses in inflammatory settings in vivo and ex vivo
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