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Clinical and Vaccine Immunology, March 2009, p. 397-407, Vol. 16, No. 3
1071-412X/09/$08.00+0     doi:10.1128/CVI.00210-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bacterial Particle Endocytosis by Epithelial Cells Is Selective and Enhanced by Tumor Necrosis Factor Receptor Ligands{triangledown}

Robin T. Clark,1 Andrew Hope,2,3 Marta Lopez-Fraga,1,4 Neal Schiller,1 and David D. Lo1,2*

Division of Biomedical Sciences, University of California, Riverside, California 92521,1 La Jolla Institute for Allergy and Immunology, La Jolla, California 92037,2 Allergy Department, Kaiser Permanente, Santa Clara, California 95051,3 Sylentis, 28760 Madrid, Spain4

Received 30 May 2008/ Returned for modification 7 August 2008/ Accepted 29 December 2008

Bacterial pathogens use virulence strategies to invade epithelial barriers, but active processes of epithelial cells may also contribute to the endocytosis of microbial particles. To focus on the latter, we studied the uptake of fixed and fluorescently labeled bacterial particles in intestinal and bronchoepithelial cell cultures and found it to be enhanced in Caco-2BBe and NCI-H292 cells after treatment with tumor necrosis factor alpha and an agonist antibody against the lymphotoxin beta receptor. Confocal fluorescence microscopy, flow cytometry, and transmission electron microscopy revealed that Staphylococcus aureus and Yersinia enterocolitica were readily endocytosed, although there was scant uptake of Shigella sonnei, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae particles. Endocytosed Staphylococcus was often associated with cytoplasmic claudin-4 vesicles; this was not found for Yersinia, suggesting that cytokine treatment upregulated two distinct endocytosis pathways. Interestingly, when Staphylococcus and Yersinia were coincubated with epithelial monolayers, the cells were unlikely to take up Yersinia unless they had also endocytosed large numbers of Staphylococcus particles, although the two bacteria were apparently processed in distinct compartments. Cytokine treatment induced an upregulation and redistribution of β1 integrin to the apical surface of NCI-H292 cells; consistent with this effect, treatment with anti-β1 integrin antibody blocked uptake of both Yersinia and Staphylococcus in NCI-H292 and Caco-2BBe cells. Our results suggest that capture of bacterial particles by mucosal epithelial cells is selective and that different endocytic mechanisms are enhanced by proinflammatory cytokines.

* Corresponding author. Mailing address: Division of Biomedical Sciences, University of California, Riverside, 900 University Ave., Riverside, CA 92521. Phone: (951) 827-4553. Fax: (951) 827-5504. E-mail: david.lo{at}ucr.edu

{triangledown} Published ahead of print on 7 January 2009.

Clinical and Vaccine Immunology, March 2009, p. 397-407, Vol. 16, No. 3
1071-412X/09/$08.00+0     doi:10.1128/CVI.00210-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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