Akt/Protein kinase B modulates macrophage inflammatory response to Francisella infection and confers a survival advantage in mice.
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-kappaB 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-kappaB, thereby contributing to immunity against F. novicida infection.
Rajaram
Murugesan V S
MV
Dorothy M. Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210, USA.
Ganesan
Latha P
LP
Parsa
Kishore V L
KV
Butchar
Jonathan P
JP
Gunn
John S
JS
Tridandapani
Susheela
S
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005603:Francisella / Q000235:genetics*; D005798:Genes, Bacterial / Q000502:physiology; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016019:Survival Analysis; D014158:Transcription, Genetic
D016207:Cytokines; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt