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Infection and Immunity, March 2004, p. 1512-1518, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1512-1518.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Increases in c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase and p38 Activity in Monocyte-Derived Macrophages following the Uptake of Legionella pneumophila

Chad T. Welsh,1 James T. Summersgill,1,2 and Richard D. Miller1*

Department of Microbiology and Immunology,1 Division of Infectious Diseases, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky2

Received 26 June 2003/ Returned for modification 4 September 2003/ Accepted 13 November 2003

Legionella pneumophila, the causative agent of Legionnaires' disease, infects and replicates within a variety of eukaryotic cells. The purpose of the current study was to examine host cell signaling events immediately following uptake and early in the endocytic process (less than 1 h) following the phagocytosis of L. pneumophila. This examination focused on the protein kinase signal pathways to identify any aberrant signal(s) induced by L. pneumophila within its host, as a means to alter the normal endocytic pathway. The mitogen-activated protein kinase cascades are of interest due to their involvement in cellular regulation. The experiments were carried out with monocyte-derived macrophages (MDMs). All three mitogen-activated protein kinase cascades were activated when MDMs were inoculated with either Legionella strain (wild-type strain AA100 or dotA mutant GL10) or an Escherichia coli control. Whereas the avirulent treatments, GL10 and E. coli, exhibited a leveling off or a return to near basal levels of phosphorylation/activity of c-Jun N-terminal kinase by 60 min, the virulent strain AA100 exhibited a significantly increased level of activity through 60 min that was greater than that seen in GL10 (P = 0.025) and E. coli (P = 0.014). A similar trend was seen with p38 phosphorylation. Phosphorylation of mitogen-activated protein/ERK kinase (MEK) was decreased in strain AA100 compared to E. coli. Inhibition of the activity of either the stress-activated protein kinase/c-Jun N-terminal kinase or p38 pathway significantly decreased the ability of legionellae to replicate intracellularly, suggesting the necessity of these two pathways in its intracellular survival and replication.

* Corresponding author. Mailing address: Dept. of Microbiology and Immunology; University of Louisville, Louisville, KY 40292. Phone: (502) 852-5360. Fax: (502) 852-6545. E-mail: richard.miller{at}louisville.edu.

Editor: B. B. Finlay

Infection and Immunity, March 2004, p. 1512-1518, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1512-1518.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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