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Secreted Giardia intestinalis cysteine proteases disrupt intestinal epithelial cell junctional complexes and degrade chemokines
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.ORCID iD: 0000-0001-7091-5570
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Univ Bern, Vetsuisse Fac, Inst Parasitol, Bern, Switzerland.
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2018 (English)In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 9, no 1, p. 879-894Article in journal (Refereed) Published
Abstract [en]

Giardiasis is a common diarrheal disease caused by the protozoan parasite Giardia intestinalis. Cysteine proteases (CPs) are acknowledged as virulence factors in Giardia but their specific role in the molecular pathogenesis of disease is not known. Herein, we aimed to characterize the three main secreted CPs (CP14019, CP16160 and CP16779), which were identified by mass spectrometry in the medium during interaction with intestinal epithelial cells (IECs) in vitro. First, the CPs were epitope-tagged and localized to the endoplasmic reticulum and cytoplasmic vesicle-like structures. Second, we showed that recombinant CPs, expressed in Pichia pastoris, are more active in acidic environment (pH 5.5-6) and we determined the kinetic parameters using fluorogenic substrates. Third, excretory-secretory proteins (ESPs) from Giardia trophozoites affect the localization of apical junctional complex (AJC) proteins and recombinant CPs cleave or re-localize the AJC proteins (claudin-1 and -4, occludin, JAM-1, beta-catenin and E-cadherin) of IECs. Finally, we showed that the ESPs and recombinant CPs can degrade several chemokines, including CXCL1, CXCL2, CXCL3, IL-8, CCL2, and CCL20, which are up-regulated in IECs during Giardia-host cell interactions. This is the first study that characterizes the role of specific CPs secreted from Giardia and our results collectively indicate their roles in the disruption of the intestinal epithelial barrier and modulating immune responses during Giardia infections.

Place, publisher, year, edition, pages
2018. Vol. 9, no 1, p. 879-894
Keywords [en]
parasite, diarrhea, tight junction, chemokine, intestinal barrier, secretion, cathepsin B, Host-pathogen interactions
National Category
Infectious Medicine Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-355478DOI: 10.1080/21505594.2018.1451284ISI: 000431949700001PubMedID: 29726306OAI: oai:DiVA.org:uu-355478DiVA, id: diva2:1229228
Funder
Swedish Research Council, 2012-03364Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-06-29Bibliographically approved

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