**7. Inhibition of apoptosis by** *Trypanosoma cruzi*

#### **7.1. Immune response to** *T. cruzi*

Chagas' disease affects nearly 8 million people in Latin America [125] and is caused by the intracellular parasite *Trypanosoma cruzi*. The infection with *T. cruzi* is characterized by an acute phase that can be controlled by the immune system of the host. Afterwards, patients can remain asymptomatic or develop a chronic phase that affects mainly the heart and peripheral nervous system [126, 127]. In some cases, patients seem asymptomatic although they present several damages. *T. cruzi* has the capacity to infect virtually any cell where infective tripomastigotes reach the cytoplasm, replicate, lyse the cell and infect other cells. One of the cells inside the mammalian host where *T. cruzi* replicates is the macrophage. These cells are crucial for the immune response against the parasite because, depending on the stimulus, can be classically or alternatively activated. Classically activated macrophages (M1) produce nitric oxide (NO) that has the capacity of killing *T. cruzi*, whereas alternatively activated macrophages, belonging to the M2 spectrum, synthesize polyamines that actually promote infection [128, 129]. Thus, one of the most important mechanisms of protective immunity against *T. cruzi* is the classical activation of macrophages for the elimination of the intracellular parasites. *T. cruzi* must control the activation of macrophages and inhibit apoptosis in order to perpetuate inside the cells. To achieve this, parasites must reduce the production of toxic molecules, including NO and its derivatives [130, 131] and must escape from the parasitophorous vacuole [132].

The development of a specific immune response against *T. cruzi* overcomes the evasion strategies displayed by the parasite. Antibodies as well as T cells are required for the control of infection [133–135], where both CD4 and CD8 T cells produce IFN-*γ* that activates macrophages to restrain infection [136, 137], while CD8 T cells eliminate cells harboring parasites in the cytoplasm and also promote immunopathology in the heart [138, 139]. Some of these mechanisms are regulated by cytokines, such as IL-10 and TGF-β, which diminish inflammation and thus pathology, but might contribute to the persistence of parasites [140, 141]. Also, it has been demonstrated that apoptosis of lymphocytes in the course of *T. cruzi* infection down regulates T-cell expansion [142, 143], B-cell response [144], parasite killing by M1 [143, 145], and CD8 T-cell-mediated immunity [146, 147]. Furthermore, infection is also promoted by the phagocytosis by macrophages of apoptotic T lymphocytes in a matter dependent of prostaglandins, TGF-*β*, and polyamine biosynthesis [148], which are characteristic of M2 activation [128]. In contrast, the blockade of prostaglandin production or the inhibition of T lymphocyte apoptosis by caspase inhibitors reduces parasite growth *in vitro* and parasitemia in an experimental model of Chagas disease [148, 149].

#### **7.2. Apoptosis modulation in** *T. cruzi* **infection**
