Cleavage of interleukin‐8 and attenuation of neutrophil chemotaxis by a Giardia cathepsin B

Abstract

Parasitic immunomodulatory molecules are currently undergoing investigation for their potential as anti‐inflammatory therapeutics. Children infected with the small intestinal parasite Giardia duodenalis have attenuated inflammatory responses via unknown mechanisms.ObjectiveTo determine if Giardia trophozoites modulate interleukin‐8 (CXCL8) secretion from intestinal epithelial cells (IECs) resulting in attenuated neutrophil (PMN) chemotaxis.ResultsCo‐incubation of Giardia trophozoites with ex vivo small intestinal mucosal biopsy tissues or in vitro monolayers resulted in attenuation of IL‐1β‐ or S. typhimurium‐induced CXCL8 secretion via parasitic cleavage of CXCL8. Giardia‐mediated cleavage of CXCL8 decreased its chemotactic ability for PMNs. Giardia trophozoites secrete cysteine proteases in the presence or absence of in vitro monolayers. Inhibition of Giardia cysteine proteases with a cysteine protease inhibitor (E‐64d) or a cathepsin B‐specific inhibitor (Ca‐074Me) inhibited Giardia‐mediated cleavage of CXCL8.ConclusionGiardia trophozoites release a cathepsin B‐like protease that cleaves CXCL8 and attenuates PMN chemotaxis. Funding provided by NSERC, AIHS, and CCFC.