The Journal of Immunology, Vol 150, Issue 10 4457-4465, Copyright © 1993 by American Association of Immunologists

ARTICLES

Alteration of Leishmania donovani infection levels by selective impairment of macrophage signal transduction

KJ Moore, S Labrecque and G Matlashewski
Institute of Parasitology, McGill University, Quebec, Canada.

Leishmania donovani is an obligate intracellular protozoan which residues and multiples in macrophages. The molecular basis for this host-parasite interaction is poorly understood. Targeting a signal transduction pathway in the macrophage would allow this parasite to manipulate cellular gene expression, and this may aid in ensuring its survival. We demonstrate that in macrophages infected with L. donovani for 18 h, c-fos gene expression mediated through protein kinase A was unaffected under conditions where there was an impairment of protein kinase C (PKC)-mediated c-fos gene expression. This selective impairment of PKC-mediated c-fos gene expression was substantially augmented in macrophages put in contact with L. donovani promastigotes or amastigotes for only 1 h. Treatment of macrophages with L. donovani- conditioned media was not sufficient to significantly impair signal transduction. These data revealed that L. donovani selectively impaired the transmission of information from the cell surface to the nucleus and that this effect is induced very soon after macrophage-parasite contact. The biologic significance of this altered signal transduction in the macrophage with respect to infection with L. donovani was then examined by treating macrophages with various protein kinase inhibitors prior to infection with amastigotes. Macrophages that were treated with PKC inhibitors demonstrated an increase in the initial uptake of the parasite and carried heavier infection levels than did controls. In contrast, treatment of macrophages with an inhibitor of calmodulin- dependent protein kinase (CaM-PK) did not show significant differences in the initial uptake of parasite, but prolonged impairment of CaM-PK resulted in a decrease in the level of macrophage infection. Further experiments revealed that promastigote proliferation was severely impaired by the CaM-PK inhibitor but not any of the other inhibitors.

This article has been cited by other articles:

				A. Mookerjee, P. C. Sen, and A. C. Ghose Immunosuppression in Hamsters with Progressive Visceral Leishmaniasis Is Associated with an Impairment of Protein Kinase C Activity in Their Lymphocytes That Can Be Partially Reversed by Okadaic Acid or Anti-Transforming Growth Factor {beta} Antibody Infect. Immun., May 1, 2003; 71(5): 2439 - 2446. [Abstract] [Full Text] [PDF]

				M. Chawla and R. A. Vishwakarma Alkylacylglycerolipid domain of GPI molecules of Leishmania is responsible for inhibition of PKC-mediated c-fos expression J. Lipid Res., March 1, 2003; 44(3): 594 - 600. [Abstract] [Full Text] [PDF]

				M. Junghae and J. G. Raynes Activation of p38 Mitogen-Activated Protein Kinase Attenuates Leishmania donovani Infection in Macrophages Infect. Immun., September 1, 2002; 70(9): 5026 - 5035. [Abstract] [Full Text] [PDF]

				S. Bhattacharyya, S. Ghosh, P. L. Jhonson, S. K. Bhattacharya, and S. Majumdar Immunomodulatory Role of Interleukin-10 in Visceral Leishmaniasis: Defective Activation of Protein Kinase C-Mediated Signal Transduction Events Infect. Immun., March 1, 2001; 69(3): 1499 - 1507. [Abstract] [Full Text] [PDF]

				S. Buates and G. Matlashewski General Suppression of Macrophage Gene Expression During Leishmania donovani Infection J. Immunol., March 1, 2001; 166(5): 3416 - 3422. [Abstract] [Full Text] [PDF]

				A. St-Denis, V. Caouras, F. Gervais, and A. Descoteaux Role of Protein Kinase C-{alpha} in the Control of Infection by Intracellular Pathogens in Macrophages J. Immunol., November 15, 1999; 163(10): 5505 - 5511. [Abstract] [Full Text] [PDF]

				D. Nandan, R. Lo, and N. E. Reiner Activation of Phosphotyrosine Phosphatase Activity Attenuates Mitogen-Activated Protein Kinase Signaling and Inhibits c-FOS and Nitric Oxide Synthase Expression in Macrophages Infected with Leishmania donovani Infect. Immun., August 1, 1999; 67(8): 4055 - 4063. [Abstract] [Full Text] [PDF]

				S. Corradin, J. Mauel, A. Ransijn, C. Sturzinger, and G. Vergeres Down-regulation of MARCKS-related Protein (MRP) in Macrophages Infected with Leishmania J. Biol. Chem., June 11, 1999; 274(24): 16782 - 16787. [Abstract] [Full Text] [PDF]

				E. Ghedin, H. Charest, W.-W. Zhang, A. Debrabant, D. Dwyer, and G. Matlashewski Inducible Expression of Suicide Genes in Leishmania donovani Amastigotes J. Biol. Chem., September 4, 1998; 273(36): 22997 - 23003. [Abstract] [Full Text] [PDF]

				W.-W. Zhang and G. Matlashewski Loss of virulence in Leishmania donovani deficient in an amastigote-specific protein, A2 PNAS, August 5, 1997; 94(16): 8807 - 8811. [Abstract] [Full Text] [PDF]