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Infection and Immunity, June 2002, p. 3040-3052, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3040-3052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Differential Regulation of the Mitogen-Activated Protein Kinases by Pathogenic and Nonpathogenic Mycobacteria

Shannon K. Roach* and Jeffrey S. Schorey*

Department of Biology, Center of Tropical Disease Research and Training, University of Notre Dame, Notre Dame, Indiana 46617

Received 26 December 2001/ Returned for modification 9 February 2002/ Accepted 12 March 2002

Mycobacteria are the etiologic agents of numerous diseases which account for significant morbidity and mortality in humans and other animal species. Many mycobacteria are intramacrophage pathogens and therefore the macrophage response to infection, which includes synthesis of cytokines such as tumor necrosis factor alpha (TNF-{alpha}) and production of nitric oxide, has important consequences for host immunity. However, very little is known about the macrophage cell signaling pathways initiated upon infection or how pathogenic mycobacteria may modulate the macrophage responses. Using primary murine bone marrow macrophages, we established that p38 and extracellular signal-regulated kinases 1 and 2 of the mitogen-activated protein kinase (MAPK) pathways are activated upon infection with different species of mycobacteria. However, we observed decreased MAPK activity over time in macrophages infected with pathogenic Mycobacterium avium strains relative to infections with nonpathogenic mycobacteria. Furthermore, macrophages infected with M. avium produced lower levels of TNF-{alpha}, interleukin 1ß, and inducible nitric oxide synthase 2 than macrophages infected with nonpathogenic species. Inhibitor studies indicate that the MAPKs are required for the Mycobacterium-mediated induction of these effector proteins. Our data indicate that MAPKs are activated in macrophages upon invasion by mycobacteria and that this activation is diminished in macrophages infected with pathogenic strains of M. avium, resulting in decreased production of important immune effector proteins. The decreased MAPK activation associated with M. avium infections suggests a novel point of immune intervention by this mycobacterial species.

* Corresponding author. Mailing address: Department of Biology, University of Notre Dame, 130 Galvin Life Science Center, Notre Dame, IN 46656. Phone: (219) 631-3734. Fax: (219) 631-7413. E-mail: schorey.1{at}nd.edu and sroach{at}nd.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, June 2002, p. 3040-3052, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3040-3052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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