**3.1 Trypanosomiasis**

Chagas is a parasitic disease caused by intracellular parasites *Trypanosoma cruzi*. The prevalence of the disease is around 6–7 million worldwide, mainly in Latin America and listed in 17 neglected tropical diseases (NTD) classified by the WHO (WHO-2021). The present chemotherapy is relay on two available drugs 5-nitrofurannifurtimox (NFX) and 2-nitroimidazole benznidazole [65]. *T. cruzi* contains only Fe-dependent superoxide dismutase (Fe-SOD). Parasites have two dimeric Fe-SOD isoforms, one mitochondrial and one cytosolic isoform. However, Mateo et al. [35] investigated and characterized 4 Fe-SODs in *T. cruzi* epimastigotes, mainly cytosolic. The level of Fe-SOD increases during the differentiation of short stumpy forms of the parasite into dividing procyclic forms [66]. Therefore, Fe-SODs could be a promising drug target for the development of anti-chagasic drugs because of their exclusivity in *T. cruzi*. Furthermore, the crystal structures of the cytosolic Fe-SOD and the mitochondrial Fe-SOD from *T. cruzi* suggest that each enzyme has two polypeptide chains and two active sites composed of a Fe2+/Fe3+ ion, respectively. In Chagas disease, phagocytosis of parasites by macrophages is the first line of defense against the parasites by the host. Macrophage produces superoxide radical (O2 •−), which diffuses into parasitophorous vacuoles, causing toxic environments to the parasites. However, *T. cruzi* is also equipped with an antioxidant network to counter the host-derived ROS activity. During infections, parasites are internalized into the phagolysosomal compartment and activate the NADPH oxidase 2 complex (Nox2) of the host macrophage [67]. Nox2 activity in macrophages results in intraphagosomal formation of oxygen free radicals (O2•−) and O2•− derived ROS, which is required to


*Superoxide Dismutase: A Key Enzyme for the Survival of Intracellular Pathogens in Host DOI: http://dx.doi.org/10.5772/intechopen.100322*

> **Table 1.**

*Distribution of superoxide dismutase (SOD) & their sub-class in various intracellular pathogens and their role in pathogenesis of respective diseases.*

neutralize parasite proliferation and disrupt its differentiation in the early stage of infection. Macrophages derived from Nox2-deficient (gp91phox−/−) mice produced marginal amounts of superoxide radical and are more susceptible to parasite infection than those macrophages derived from wild-type mice. Nox2-derived superoxide radical plays a crucial role in controlling *T. cruzi* infection in the early phase of a murine model of Chagas disease [68]. Inhibition or ablation of the Nox2 enzyme has shown to be detrimental for controlling the infection of a number of pathogens *in vitro* and *in vivo* [69, 70].

*Trypanosoma brucei* is an obligate intracellular protozoan parasite that causes sleeping sickness in humans in many countries of sub-Saharan Africa. Various sub-species of parasites cause the disease and responsible for more than 90% of all trypanosomal diseases in humans [71]. Overexpression of SOD-B1 in *T. brucei* has shown hypersensitivity to a trypanocidal agent such as benznidazole and gentian violet. A similar study in *L. chagasi* revealed that an increase in SOD-B1 protein leads to resistance toward paraquat and nitroprusside [72]. Deleting one copy of Sod-B1 gene in the *L. chagasi* increased the sensitivity to the drug and a significantly decreased the parasites survival within the host macrophage. *T. brucei* serves four SOD isoforms, of which three are iron-dependent, which is typically very much similar to prokaryotic SODs. Localization studies reveal that out of four SOD, two are predominantly found in the glycosome (*Tb*SOD-B1 and *Tb*SOD-B2), and the other two are found in mitochondria (*Tb*SOD-A and *Tb*SOD-C) [30]. Overexpression of cytosolic Fe-SOD-B of *T cruzi* showed more resistance to the phagocytic killing of macrophages and increased intracellular proliferation than wild-type (WT) parasites. Fe-SOD-B overexpressed mutant parasites showed higher infectivity than WT but lost in gp91-phox−/− macrophages, emphasizing the role of O2 •− in parasite killing [67]. *Tc*FeSOD-A gene amplification increases the *Tc*FeSOD protein expression and enzyme activity in a *T. Cruzi* induced resistance to benznidazole and gentian violet treatments [73]. The reduced expression of *Tb*SOD-B leads to rapid accumulation of superoxide anion within the trypanosome responsible for detoxifying highly toxic radical in the parasite [74].
