Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis.
Infection with the intracellular parasite Toxoplasma gondii renders cells resistant to multiple pro-apoptotic signals, but underlying mechanisms have not been delineated. The phosphoinositide 3-kinase ( PI 3-kinase) pathway and the immediate downstream effector protein kinase B (PKB/Akt) play important roles in cell survival and apoptosis inhibition. Here, we show that Toxoplasma infection of mouse macrophages activates PKB/Akt in vivo and in vitro. In a mixed population of infected and non-infected macrophages, activation is only observed in parasite-infected cells. The PI 3-kinase inhibitors wortmannin and LY294002 block parasite- induced PKB phosphorylation. PKB activation occurs independently of Toll-like receptor adaptor protein MyD88 but uncoupling of Gi-protein- mediated signaling with pertussis toxin prevents PKB phosphorylation. Moreover, in the presence of PI 3-kinase inhibitors or pertussis toxin, not only PKB activation but also ERK1/2 activation during T. gondii infection is defective. Most importantly, the parasite's ability to induce macrophage resistance to pro-apoptotic signaling is prevented by incubation with PI 3-kinase inhibitors. This study demonstrates that T. gondii exploits host Gi-protein-dependent PI 3-kinase signaling to prevent induction of apoptosis in infected macrophages.[1]References
- Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis. Kim, L., Denkers, E.Y. J. Cell. Sci. (2006) [Pubmed]
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