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Infect Immun, March 1998, p. 1106-1112, Vol. 66, No. 3
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Listeria monocytogenes Invasion of Epithelial Cells Requires the MEK-1/ERK-2 Mitogen-Activated Protein Kinase Pathway

Patrick Tang,1,2 Claire L. Sutherland,2 Michael R. Gold,2 and B. Brett Finlay1,2,3,*

The Biotechnology Laboratory1 and the Departments of Microbiology and Immunology2 and Biochemistry and Molecular Biology,3 University of British Columbia, Vancouver, British Columbia, Canada

Received 24 September 1997/Returned for modification 27 October 1997/Accepted 16 December 1997

PD98059, a specific inhibitor of MEK-1 mitogen-activated protein (MAP) kinase kinase, blocked Listeria monocytogenes invasion into HeLa epithelial cells. The effects of PD98059 were reversible, as adherent extracellular bacteria were internalized upon removal of the drug. Previously, we reported that L. monocytogenes could activate ERK-1 and ERK-2 MAP kinases through the action of listeriolysin O (LLO) on the host cell (P. Tang, I. Rosenshine, P. Cossart, and B. B. Finlay, Infect. Immun. 64:2359-2361, 1996). We have now found that two other MAP kinase pathways, those of p38 MAP kinase and c-Jun N-terminal kinase, are also activated by wild-type L. monocytogenes. Mutants lacking functional LLO (hly mutants) were still invasive but only activated ERK-2 and only activated it at later (90-min) postinfection times. Two inhibitors of L. monocytogenes invasion, cytochalasin D, which disrupts actin polymerization, and wortmannin, which blocks phosphatidylinositol (PI) 3-kinase activity, did not block ERK-2 activation by wild-type L. monocytogenes and hly mutants. However, genistein, an inhibitor of tyrosine kinases, and PD98059 both blocked invasion and decreased ERK-2 activation. These results suggest that MEK-1 and ERK-2 activities are essential for L. monocytogenes invasion into host epithelial cells. This is the first report to show that a MAP kinase pathway is required for bacterial invasion.


* Corresponding author. Mailing address: Biotechnology Laboratory, #237-6174 University Blvd., University of British Columbia, Vancouver, B.C., Canada V6T 1Z3. Phone: (604) 822-2210. Fax: (604) 822-9830. E-mail: bfinlay{at}unixg.ubc.ca.




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