**5.1 Cryptococcosis**

*Cryptococcus neoformans* (*Cn*) is a facultative intracellular fungal pathogen and can propagate inside the host macrophages during many stages of experimental and human infections [136, 137]. *Cryptococcus* is a soil fungus that causes lifethreatening meningitis in immunocompromised patients [138, 139]. *Cryptococcus* is an encapsulated pathogenic yeast composed primarily of glucuronoxylomannan (GXM). This polysaccharide helps the fungus play a defensive and offensive role during pathogenesis. It protects the fungus against phagocytosis and promoting intracellular pathogenesis through the cytotoxic release of polysaccharides into macrophage vacuoles [136]. *Cryptococcus* rarely causes clinically visible infections in healthy hosts, but it can be present in latency and persistence inside macrophages *Superoxide Dismutase: A Key Enzyme for the Survival of Intracellular Pathogens in Host DOI: http://dx.doi.org/10.5772/intechopen.100322*

[61, 62]. *C. neoformans var. gattii* predominantly infects individuals having a normal immune response, whereas var. grubii and neoformans are common in immunocompromised individuals. *C. neoformans var. gattii* hinders macrophage phagocytic response, whereas the other two varieties are readily killed by ROS released by phagocytic cells [140, 141].

*C. neoformans* is resistance to ROS mediated oxidative killing of macrophage by inducing the SOD activity and might be playing an important role in virulence of this fungus. Exogenous supplementation of SOD significantly controlled the bacterial growth by inducing human neutrophil function, suggesting that SOD plays a protective role during *C. neoformans* infection [63]. *Cryptococcus neoformans* var. *gattii* contains two types of SODs such as copper, zinc-depend SOD (SOD1) and Mn-dependent (SOD2) isoenzymes [142]. Both SOD1 and SOD2 are intracellular SODs, and deletion of their encoding genes reduces the fungal virulence in vivo model of infection. Furthermore, the mutant fungus also increases sensitivity to pharmacologically-induced intracellular oxidative stress [143]. The sod1 mutant *C. neoformans* was shown three characteristic features 1) highly sensitivity toward oxidative killing by human polymorphonuclear (PMN) cells and by the redox cycling agent menadione. 2) The sod1 mutant was markedly attenuated in virulence when raising the infection in mice, and it also showed significantly susceptibility to in vitro killing by human neutrophils. 3) SOD1 deletion also appeared to be defects in the expression of a number of virulence factors such as laccase, urease, and phospholipase. Complementation of the sod1 gene mutant *C. neoformans* with SOD1 protein regained the virulence factor and menadione resistance. Hence, the antioxidant function of SOD1 is critical for the pathogenesis of the fungus during intracellular survival [60, 141, 144].

#### **5.2 Histoplasmosis**

*Histoplasma capsulatum* is an intracellular fungal pathogen structurally similar to yeast cells. *H. capsulatum* successfully infect host cells like neutrophils and macrophages. *H. capsulatum* is prevalent in the Midwestern United States and Latin America. Macrophages efficiently phagocytize the *Histoplasma* cells, but they failed to kill the fungus despite having ample ROS production. *Histoplasma* cells counter the ROS-mediated oxidative stress of the host by three proteins that are possibly involved in defending *Histoplasma* from ROS. sod1 and sod3 gene deficient *Histoplasma* strains shown the spatial specificity of the SOD1 and SOD3 superoxide dismutases for internal and external (i.e., host-derived) superoxide, respectively. SOD-3 is the primary source of extracellular SODs, and its expression is significantly enriched in the pathogenic phase of fungus cells. *Histoplasma* SOD-3 offers higher resistance of fungus against the phagocytic killing of host cells leading to increased capacity to cause disease in immunocompetent hosts. In *in vivo* studies, sod-3 gene deficient *Histoplasma* strains were shown the attenuation in virulence in mice. Furthermore, restoration of ∆sod3 mutant *Histoplasma* virulence in mice unable to produce superoxide radicals conclusively proves that SOD3 functions in the detoxification of superoxide generated by the host. SOD-3 also prevents the superoxide-dependent killing of *Histoplasma* yeast cells. The host to control the infection of *Histoplasma* requires ROS production. Hence, SOD-3 is a central virulence factor of *Histoplasma* and help to fungus survives under oxidative stress produced by host phagocytic cells during infection [64].
