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Role of Protein Kinase C- in the Control of Infection by Intracellular Pathogens in Macrophages¹

Anik St-Denis^*, Vassiliki Caouras, Francine Gervais and Albert Descoteaux^2,*

^* INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada; and Centre for the Study of Host Resistance, McGill University, Montréal, Québec, Canada

The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In this study, we investigated the role of macrophage PKC- in the uptake and subsequent fate of Leishmania donovani promastigotes and Legionella pneumophila infections. To this end, we used clones of the murine macrophage cell line RAW 264.7 overexpressing a dominant-negative (DN) mutant of PKC-. While phagocytosis of L. donovani promastigotes was not affected by DN PKC- overexpression, their intracellular survival was enhanced by 10- to 20-fold at 48 h postinfection. Intracellular survival of a L. donovani mutant defective in lipophosphoglycan repeating units synthesis, which normally is rapidly degraded in phagolysosomes, was enhanced by 100-fold at 48 h postinfection. However, IFN--induced leishmanicidal activity was not affected by DN PKC- overexpression. Similar to macrophages from genetically resistant C57BL/6 mice, control RAW 264.7 cells were not permissive for the intracellular replication of Legionella pneumophila. In contrast, DN PKC--overexpressing RAW 264.7 clones were phenotypically similar to macrophages from genetically susceptible A/J mice, as they allowed intracellular replication of L. pneumophila. Permissiveness to L. pneumophila was not the consequence of a general defect in the microbicidal capacities because killing of a temperature-sensitive mutant of Pseudomonas aeruginosa was normal in DN PKC--overexpressing RAW 264.7 clones. Collectively, these results support a role for PKC- in the regulation of innate macrophage functions involved in the control of infection by intracellular parasites.

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