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* Dorothy M. Davis Heart and Lung Research Institute,
Ohio State Biochemistry Program, and
Department of Molecular Virology, Immunology and Medical Genetics and Center for Microbial Interface Biology, Ohio State University, Columbus, OH 43210
The Gram-negative bacterium Francisella novicida infects primarily monocytes/macrophages and is highly virulent in mice. Macrophages respond by producing inflammatory cytokines that confer immunity against the infection. However, the molecular details of host cell response to Francisella infection are poorly understood. In this study, we demonstrate that F. novicida infection of murine macrophages induces the activation of Akt. Inhibition of Akt significantly decreases proinflammatory cytokine production in infected macrophages, whereas production of the anti-inflammatory cytokine IL-10 is enhanced. Analysis of the mechanism of Akt influence on cytokine response demonstrated that Akt promotes NF-
B activation. We have extended these findings to show that Akt activation may be regulated by bacterial genes associated with phagosomal escape. Infection with mglA mutants of F. novicida elicited sustained activation of Akt in comparison to cells infected with wild-type F. novicida. Concomitantly, there was significantly higher proinflammatory cytokine production and lower IL-10 production in cells infected with the mglA mutant. Finally, transgenic animals expressing constitutively active Akt displayed a survival advantage over their wild-type littermates when challenged with lethal doses of F. novicida. Together, these observations indicate that Akt promotes proinflammatory cytokine production by F. novicida-infected macrophages through its influence on NF-B, thereby contributing to immunity against F. novicida infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants U54-AI-057153, R01 AI059406, and P01 CA095426 from the National Institutes of Health. J.P.B. is supported by National Institutes of Health Training Grant T32 CA090223.
2 Address correspondence and reprint requests to Dr. Susheela Tridandapani, Dorothy M. Davis Heart and Lung Research Institute, Room 405B, 473 West 12th Avenue, Columbus, OH 43210. E-mail address: tridandapani.2{at}osu.edu
3 Abbreviations used in this paper used: PIP3, phosphatidylinositol 3,4,5-trisphosphate; BMM, bone marrow macrophage; LVS, live vaccine strain; PDGF, platelet-derived growth factor; Myr, myristoylated.
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