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

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

the secretion of granzyme proteases, it is not surprising the blockage of this pathway by the parasite. Hence, *T. gondii* has been demonstrated to protect their host cells from Granzyme B-induced apoptosis, involving a mechanism by which the parasite abrogates the activity of

Signaling Pathways Targeted by Protozoan Parasites to Inhibit Apoptosis

http://dx.doi.org/10.5772/intechopen.76649

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In the mammalian host, *Plasmodium* parasites infect primarily hepatocytes and erythrocytes, and modulation of apoptosis by this parasite in both host cell types has been found to be crucial during infection. After transmission by the *Anopheles* mosquito, *Plasmodium* sporozoites are rapidly transported to the liver, where they invade and develop within hepatocytes before reaching erythrocytes [168]. In the liver, sporozoites transmigrate through the cytosol of multiple hepatocytes, causing wounding in the traversed cells with the release of the hepatocyte growth factor (HGF), which helps the parasite to reach a final hepatocyte in which it will reside and multiply [158, 169, 170]. It has been proposed that HGF binds to the c-mesenchymal-epithelial transition factor (c-Met) located on the surface of hepatocytes, a process that leads to PI3-K activation and a further protection of these cells from apoptosis [171, 172]. Albeit PI3-K activation trough HGF/c-Met signaling has been proposed to protect hepatocytes from apoptosis during early liver stages of infection with *Plasmodium*, other data suggest that PI3-K activation is not required to maintain this

During the blood stage of infection with *Plasmodium*, in which merozoites invade erythrocytes, multiple changes are induced in the host cell by the parasite in order to satisfy its nutritional requirements [164]. One of these changes is the activation of Ca2+ permeable channels in the plasmatic membrane of erythrocytes and the posterior entry of Ca2+ into these cells. An increase in the intracellular concentration of Ca2+ in erythrocytes has been demonstrated to induce a type of programmed cell death called eryptosis, which is characterized by cell shrinkage, cell membrane blebbing, and exposure of phosphatidyl serine, resembling apoptosis [174]. Due that infection with *Plasmodium* leads to the entry of Ca2+ into the erythrocytes and that the increment of the concentration of this ion stimulates eryptosis, it has been shown that *Plasmodium* can delay the execution of this programmed cell death mechanism by seques-

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

Granzime B in the infected cells [167].

antiapoptotic state [173].

**10. Conclusion**

**9. Apoptosis inhibition in** *Plasmodium* **spp. infection**

tering free Ca2+ ions present in the cytosol of erythrocytes [175].

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 presence increases as the parasite replicates [162].

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

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

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 the secretion of granzyme proteases, it is not surprising the blockage of this pathway by the parasite. Hence, *T. gondii* has been demonstrated to protect their host cells from Granzyme B-induced apoptosis, involving a mechanism by which the parasite abrogates the activity of Granzime B in the infected cells [167].
