Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 10, Pages 2119-2126Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.02934
Keywords
monocytes/macrophages; parasitic-protozoan; signal transduction; apoptosis
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Funding
- NIAID NIH HHS [AI50617] Funding Source: Medline
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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 noninfected 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 G(i)-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 G(i)-protein-dependent PI 3-kinase signaling to prevent induction of apoptosis in infected macrophages.
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