**4. Role of SOD in intracellular bacteria**

There are several intracellular bacteria which are causing severe illness in human's beings and if left untreated 100% mortality. Most pathogenic bacteria contain MnSOD or FeSOD in their cytoplasm, while CuZnSOD has been found on the periplasm of pathogenic bacteria and played an essential role during phagocytosis [11, 23]. In addition to their ability to detoxify free radicals during aerobic growth, bacterial SODs are also critical in determining the virulence factors. In several intracellular bacterial infections, SOD-C acts as a critical virulence factor, and its localization to the periplasmic membrane protects bacteria from ROS derived from host cells [49, 98–100]. Moreover, many virulent bacteria maintain two copies of the sodC gene [101]. The evolutionary maintenance of an extra sodC gene copy indicates that SOD is essential for pathogenic bacteria for their survival inside the host niche [101]. These pathogens belong to the categories of genus *Mycobacterium, Salmonella, Staphylocccus* and *Francisella*, causing spectrum of disease like tuberculosis, leprosy, typhoid, boils, furuncles, cellulitis and tularemia etc. **Table 1**.

#### **4.1 Tuberculosis and leprosy**

*Mycobacterium* is an intracellular bacterium, which is causing two distinct disease manifestations in humans, such as Tuberculosis and Leprosy. Tuberculosis (TB) is caused by *M. tuberculosis*, a leading infectious agent that claims millions of deaths worldwide/year [102]. *M. tuberculosis* is encountered several exogenous and endogenous redox pressures throughout its pathogenic life cycle. Therefore, they use various in-house enzymes to detoxify and neutralize the redox potential produced by host cells. Catalase–Peroxidase, Superoxide dismutase, and Alkyl Hydroperoxidase are the enzymes involved in the clearance of oxidative stress [47].

*M. Tuberculosis* is a highly pathogenic bacterium contains Fe-SOD and expresses 93-fold more superoxide dismutase. In contrast, non-pathogenic mycobacterium *M. Smegmatis* has Mn-SOD, and *M. Tuberculosis* export more enzyme than *M. smegmatis* [48]. Superoxide dismutase (SOD) of *M. tuberculosis* is a 207-residue enzyme with molecular mass of 23 kDa [103]. Treatment with diethyldithiocarbamate, a potent inhibitor of SOD, increased *M. lepraemurium* survival in murine splenic macrophages [104], suggesting that SOD protein is required for the long-term survival of mycobacterium in vivo [104] *M. tuberculosis* has two distinct SOD proteins, SOD-A and SOD-C. SOD-A is one of the main extracellular proteins contains Mn, Fe-SOD. SOD-C is much lower protein contains Cu, Zn SOD, and present in the outer membrane of the bacteria. SOD-C was upregulated during phagocytosis by macrophage, suggesting its importance in protecting the *M. tuberculosis* membrane against damage from superoxide radicals [25]. SOD of *M. tuberculosis* scavenge oxygen free radicals and inhibits the release of NO by inhibiting iNOS activity. It impairs acquired by down-regulating the IFN-γ expression as well as control the caspase-dependent apoptosis. SOD also inhibits innate immunity by down-regulating TLR2 expression as well as control the TLR2 dependent signaling in the cells [104].

*Mycobacterium leprae is* the causative agent of leprosy or Hansen's disease. *M. leprae* is the single known bacterial pathogen that infects superficial peripheral nerves. It is an intracellular pathogen that infects both myelinated and nonmyelinated Schwann cells of the nerve and proliferates within the monocyte/macrophage series cells. Peripheral nerves are not protected from the immune response of host due to the blood–brain barrier [105]. Hence, the advantage of *M. leprae* is to escape from the

phagocytosis actions of the macrophage may be a critical factor in its pathogenicity [106]. The SOD activity of *M. leprae* is lower than the other mycobacteria species such as *M. lepraemurium, M. phlei* [107]. Therefore, the ability to clear the *M. leprae* infection via SOD pathway appeared to be a distinct mannerism and is not dependent on macrophage activation and differentiation.
