**10. Conclusion**

**8. Apoptosis inhibition in** *Toxoplasma gondii* **infection**

106 Current Understanding of Apoptosis - Programmed Cell Death

presence increases as the parasite replicates [162].

(PKB/Akt), which acts as an apoptosis inhibitor of the host cells [165].

caspases, for example, caspase 3 and caspase 7 [166].

*Toxoplasma gondii* is an obligate intracellular parasite capable to infect almost all types of nucleated cells and has developed multiple mechanisms to avoid immune elimination. It has been reported that this parasite can modulate multiple signaling pathways in their host cells in order to inhibit apoptosis, ensuring in this way its survival and persistence during infection. As a clear example of this process, different evidences have shown a failure in the activation of caspase 8,

The activation of the NF-κB transcription factor has been pointed as a pivotal mechanism used by *T. gondii* to inhibit apoptosis in several host cell types [157, 159, 160]. Following infection, it has been described that *T. gondii* induces NF-κB translocation into the nucleus, where this factor induces the transcriptional upregulation of genes that codify for antiapoptotic proteins that belong to the Bcl-2 and IAP families [157, 159, 160]. The translocation of NF-κB to the nucleus and subsequent gene transcription is clearly dependent of the host cell IκB kinase (IKK), which phosphorylates the IκB inhibitor molecules that maintain NF-κB inactive, allowing after this phosphorylation the activation and nuclear translocation of this transcription factor. However, in *T. gondii-*infected cells, the existence of a novel parasite-derived IκB kinase (TgKK) has been identified at the parasitophorous membrane together with phosphorylated IκB molecules [161]. In this sense, both host IKK and TgIKK cooperate for a continuous NF-κB activation during infection, in a process in which the host IKK could be inducing the initial phosphorylation of IκB molecules, followed by a sustained participation of the TgIKK, which

Besides the NF-κB-dependent inhibition of apoptosis during infection with *T. gondii*, an inhibition of caspase 9 and caspase 3 activation through a direct blockage, exerted by the parasite, of apoptosome formation and cytochrome c release has been proposed [156, 162]. In this regard, the *T. gondii*-dependent inhibition of cytochrome c release from the mitochondria is associated with a parasite direct degradation of the proapoptotic proteins Bad and Bax, without affecting the mRNA levels for these proteins in the host cell, a fact that suggests that the parasite is able to block directly antiapoptotic proteins of the Bcl-2 family in a host cell transcription machinery-independent process [163, 164]. Additionally, among other signaling pathways hijacked by *T. gondii* to tilt the balance of the Bcl-2 family proteins toward an antiapoptotic state of the host cell during infection, the modulation of the PI3-K/PKB/Akt pathway has been involved [155, 165]. In *T. gondii*-infected macrophages, it has been documented that this parasite activates PI3-Kinase (PI3-K), which in turns phosphorylates protein kinase B

In addition to the inhibition of apoptosis by *T. gondii* via the mitochondrial pathway, this parasite has also been reported to mediate the inhibition of apoptosis through the extrinsic pathway [166]. In this regard, it has been demonstrated that during infection, *T. gondii* can inhibit Fas/CD95-triggered apoptosis in host cells by inducing an aberrant processing and degradation of the initiator caspase 8, a process that results in a decrease in the recruitment of this protease to the death-inducing signaling complex and the inability to activate effector

Due to the fact that host defense in chronic infections due to *T. gondii* is critically dependent on the cytotoxic activity of CD8 T cells, which induce apoptosis of the infected cells via

caspase 9, and caspase 3 after apoptosis induction in *T. gondii* infected cells [155–158].

Both apoptosis and its inhibition are fundamental biological processes for the homeostasis of an organism. Both processes are present throughout life and are essential for growth, development, and reproduction. Studies on the molecular mechanisms that inhibit apoptosis have been carried out in order to elucidate the specific signaling pathways that take place during apoptosis inhibition. Up to date, various routes implicated in apoptosis activation or inhibition have been rooted out; however, there is still much to be found. Ironically, the same pathways that are involved in homeostasis and health participate in cell death processes that occur during infections and function as a defense mechanism against intracellular pathogens. In counterpart, microorganisms have developed a wide array of strategies to evade apoptosis of their host cell. Some of these strategies involve the hijacking of signaling pathways that participate in apoptosis. The better understanding and gaining of knowledge on these intracellular circuits and the physiopathology behind them will permit the development of new strategies and drugs to effectively treat the pertaining diseases mentioned in this work.

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