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Infection and Immunity, July 2002, p. 3673-3680, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3673-3680.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Strain-Dependent Induction of Enterocyte Apoptosis by Giardia lamblia Disrupts Epithelial Barrier Function in a Caspase-3-Dependent Manner

Alex C. Chin,1 Desiree A. Teoh,1 Kevin G.-E. Scott,1 Jonathon B. Meddings,2 Wallace K. Macnaughton,3,4 and Andre G. Buret1,4*

Departments of Biological Sciences,1 Medicine,2 Physiology and Biophysics,3 Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, Canada T2N 1N44

Received 14 December 2001/ Returned for modification 28 January 2002/ Accepted 21 March 2002

We recently demonstrated that Giardia lamblia rearranges cytoskeletal proteins and reduces transepithelial electrical resistance. The effect of G. lamblia on enterocyte apoptosis is unknown, and a possible link between microbially induced enterocyte apoptosis and altered epithelial permeability has yet to be established. The aim of this study was to assess whether G. lamblia induces enterocyte apoptosis in duodenal epithelial monolayers and whether this effect increases epithelial permeability. Monolayers of nontransformed human duodenal epithelial cells were incubated with sonicated or live G. lamblia trophozoites (NF, S2, WB, or PB strains) for 8, 24, and 48 h. Cell cultures were assessed for apoptosis by Hoechst fluorescence staining, enzyme-linked immunosorbent assay for apoptotic nucleosomes, and electron microscopy. In separate experiments, monolayers were pretreated with or without 120 µM caspase-3 inhibitor (Z-DEVD-FMK) for 1 h and were assessed for production of apoptotic nucleosomes, tight junctional integrity (with fluorescent ZO-1 staining followed by confocal laser microscopy), and transepithelial permeability for fluorescein isothiocyanate-dextran. G. lamblia strains NF and S2, but not strains WB or PB, induced enterocyte apoptosis within the monolayers, and this effect was inhibited by Z-DEVD-FMK pretreatment. Using the G. lamblia NF isolate, additional experiments investigated the possible link between enterocyte apoptosis and altered epithelial permeability. G. lamblia NF disrupted tight junctional ZO-1 and increased epithelial permeability, but these effects were also prevented by pretreatment with the caspase-3 inhibitor. These findings indicate that strain-dependent induction of enterocyte apoptosis may contribute to the pathogenesis of giardiasis. This effect is responsible for a loss of epithelial barrier function by disrupting tight junctional ZO-1 and increasing permeability in a caspase-3-dependent manner.

* Corresponding author. Mailing address: Department of Biological Sciences, University of Calgary, 2500 University Dr. N.W., Calgary, Alberta T2N 1N4, Canada. Phone: (403) 220-8573. Fax: (403) 289-9311. E-mail: aburet{at}ucalgary.ca.

Editor: B. B. Finlay

Infection and Immunity, July 2002, p. 3673-3680, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3673-3680.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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