Toxoplasma gondiitriggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis

Abstract

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.

Host cell manipulation by the human pathogen Toxoplasma gondii

“…However, a GiPCR signaling pathway seems to play a crucial role in the migratory phenotype [116]. This observation provides a potential mechanistic link to the previous report that T. gondii modulation of the GiPCR signaling pathway is involved in maintaining the host cells in an anti-apoptotic state [113].…”

“…The Akt/ PKB activity is linked with the promotion of the NF-κB pathway [112]. Infection of mice with T. gondii leads to the increase of the phosphorylation of Akt/PKB in macrophages containing parasites [113]. In vitro experiments reveal that the levels of activated PKB, MEK1/2 and Erk1/2 are increased in macrophages and splenic cells infected with T. gondii in a manner dependant upon the PI3K and Gi protein-coupled transmembrane receptors (GiPCR) ( Figure 2).…”

“…Indeed, inhibition of PI3K or GiPCR diminishes the phosphorylation of PKB, MEK1/2 and Erk1/2 and in the inactivation of the executioner caspase 3 in cells infected by T. gondii. In spite of that, the role of MEK1/2 and ERK1/2 in the blockade of apoptosis seems to be minor, since the specific inhibition of this pathway does not have consequences on the anti-apoptotic state induced by T. gondii infection [113].…”

Toxoplasma gondiiGenotype Determines MyD88-Dependent Signaling in Infected Macrophages

“…We confirmed the effectiveness of the toxin by examining activation of protein kinase B (PKB) that depends on G i protein signaling during RH infection ( Fig. 2C) (41).…”

A Review: Competence, Compromise, and Concomitance—Reaction of the Host Cell To Toxoplasma gondii Infection and Development

“…Toxoplasma gondii activates PI3-kinase through the signal pathway transmitted by the heterotrimer of Gi protein, resulting in the phosphorylation of PKB/Akt and ERK1/2 MAPK. Both in vitro and in vivo experiments have demonstrated that after mouse phagocytes are infected by T. gondii, the PKB/Akt pathway is activated, and the induction of apoptosis in infected macrophages is prevented (Kim and Denkers, 2006).…”