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Infection and Immunity, February 2005, p. 1171-1179, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.1171-1179.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Fusobacterium nucleatum Increases Collagenase 3 Production and Migration of Epithelial Cells

Veli-Jukka Uitto,1,2* Daniel Baillie,1 Qiang Wu,1 Renee Gendron,3 Daniel Grenier,3 Edward E. Putnins,1 Arja Kanervo,4 and James D. Firth1

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia,1 Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec City, Québec, Canada,3 Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital,2 Anaerobe Reference Laboratory, National Public Health Institute, Helsinki, Finland4

Received 28 June 2004/ Returned for modification 29 July 2004/ Accepted 2 October 2004

Fusobacterium nucleatum is closely associated with human periodontal diseases and may also be a causative agent in other infections, such as pericarditis, septic arthritis, and abscesses of tonsils and liver. Initiation and outcome of infective diseases depend critically on the host cell signaling system altered by the microbe. Production of proteinases by infected cells is an important factor in pericellular tissue destruction and cell migration. We studied binding of F. nucleatum to human epithelial cells (HaCaT keratinocyte line) and subsequent cell signaling related to collagenase 3 expression, cell motility, and cell survival, using a scratch wound cell culture model. F. nucleatum increased levels of 12 protein kinases involved in cell migration, proliferation, and cell survival signaling, as assessed by the Kinetworks immunoblotting system. Epithelial cells of the artificial wound margins were clearly preferential targets of F. nucleatum. The bacterium colocalized with lysosomal structures and stimulated migration of these cells. Of the 13 anaerobic oral bacterial species, F. nucleatum and Fusobacterium necrophorum were among the best inducers of collagenase 3 mRNA levels, a powerful matrix metalloproteinase. Production of collagenase 3 was detected in fusobacterium-infected cells and cell culture medium by immunocytochemistry, immunoblotting, and zymography. The proteinase production involved activation of p38 mitogen-activated protein kinase in the infected cells. The study suggests that F. nucleatum may be involved in the pathogenesis of periodontal diseases (and other infections) by activating multiple cell signaling systems that lead to stimulation of collagenase 3 expression and increased migration and survival of the infected epithelial cells.

* Corresponding author. Mailing address: University of Helsinki, Institute of Dentistry, PL 41, FIN-00014 University of Helsinki, Finland. Phone: 604 822 5996. Fax: 604 822 3562. E-mail: jukka.uitto{at}helsinki.fi.

Editor: F. C. Fang

Infection and Immunity, February 2005, p. 1171-1179, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.1171-1179.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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