title: Giardia duodenalis cathepsin B proteases degrade intestinal epithelial interleukin-8 and attenuate interleukin-8-induced neutrophil chemotaxis.
abstract: Giardia duodenalis (syn. G. intestinalis, G. lamblia) infections are a leading cause of waterborne diarrheal disease that can also result in the development of postinfectious functional gastrointestinal disorders via mechanisms that remain unclear. Parasite numbers exceed 10(6) trophozoites per centimeter of gut at the height of an infection. Yet the intestinal mucosa of G. duodenalis-infected individuals is devoid of signs of overt inflammation. G. duodenalis infections can also occur concurrently with infections with other proinflammatory gastrointestinal pathogens. Little is known of whether and how this parasite can attenuate host inflammatory responses induced by other proinflammatory stimuli, such as a gastrointestinal pathogen. Identifying hitherto-unrecognized parasitic immunomodulatory pathways, the present studies demonstrated that G. duodenalis trophozoites attenuate secretion of the potent neutrophil chemoattractant interleukin-8 (CXCL8); these effects were observed in human small intestinal mucosal tissues and from intestinal epithelial monolayers, activated through administration of proinflammatory interleukin-1β or Salmonella enterica serovar Typhimurium. This attenuation is caused by the secretion of G. duodenalis cathepsin B cysteine proteases that degrade CXCL8 posttranscriptionally. Furthermore, the degradation of CXCL8 via G. duodenalis cathepsin B cysteine proteases attenuates CXCL8-induced chemotaxis of human neutrophils. Taken together, these data demonstrate for the first time that G. duodenalis trophozoite cathepsins are capable of attenuating a component of their host's proinflammatory response induced by a separate proinflammatory stimulus.
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, AB, Canada Inflammation Research Network, University of Calgary, Calgary, AB, Canada Host-Parasite Interactions, University of Calgary, Calgary, AB, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Cotton
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, AB, Canada Inflammation Research Network, University of Calgary, Calgary, AB, Canada Host-Parasite Interactions, University of Calgary, Calgary, AB, Canada.
authors.forename: Amol
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Inflammation Research Network, University of Calgary, Calgary, AB, Canada Department of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Ferraz
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Yates
authors.affiliation: Inflammation Research Network, University of Calgary, Calgary, AB, Canada Department of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Beck
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, AB, Canada Inflammation Research Network, University of Calgary, Calgary, AB, Canada Host-Parasite Interactions, University of Calgary, Calgary, AB, Canada aburet@ucalgary.ca.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
mesh_terms: D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D003424:Crohn Disease / Q000378:metabolism; D016829:Giardia lamblia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000469:parasitology; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases; D012486:Salmonella typhimurium
chemical_list: D016209:Interleukin-8; D010447:Peptide Hydrolases
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