Iron-cofactored Superoxide Dismutase Inhibits Host Responses toMycobacterium tuberculosis

Abstract

Superoxide dismutase (SOD) is a ubiquitous metalloenzyme in aerobic organisms that catalyzes the conversion of superoxide anion to hydrogen peroxide. Mycobacterium tuberculosis is unusual in that it secretes large quantities of iron-cofactored SOD. To determine the role of SOD in pathogenesis, we constructed mutants of M. tuberculosis H37Rv with reduced SOD production. Compared with controls, SOD-diminished isolates were more susceptible to killing by hydrogen peroxide. The isolates were markedly attenuated, exhibiting nearly 100,000-fold fewer bacilli than virulent control strains in the lungs and spleens of C57BL/6 mice 4 wk after intravenous inoculation. In the lung, SOD-attenuated M. tuberculosis induced robust interstitial mononuclear cell infiltration within 24 h and many cells were apoptotic by TUNEL staining, whereas virulent H37Rv exhibited minimal early inflammatory response and only rare interstitial mononuclear cell apoptosis. During prolonged infections, C57BL/6 mice tolerated SOD-attenuated M. tuberculosis better than BCG, exhibiting 68% greater weight gain, quicker eradication of bacilli from the spleen, and less alveolar lung infiltration. These results establish the importance of SOD in the pathogenesis of tuberculosis. Its effect appears to be mediated in part by inhibiting innate host immune responses, including early mononuclear cell infiltration of infected tissues and apoptosis.

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…In contrast, the long-term in vivo survival studies using proapoptosis Mtb mutants show that host cell apoptosis induction is beneficial to host survival overall (Edwards et al 2001;Velmurugan et al 2007;Sun et al 2013). Mice infected with the nuoG Mtb mutant survive longer and have lower bacterial burden in the lungs during the persistent phase of the infection (Velmurugan et al 2007).…”

“…Mice infected with the nuoG Mtb mutant survive longer and have lower bacterial burden in the lungs during the persistent phase of the infection (Velmurugan et al 2007). The knockdown of superoxide dismutase A (SodA) resulted in increased apoptosis of host cells in mouse lungs and decreased virulence of the bacteria (Edwards et al 2001). SodA is secreted via the SecA2 secretion system in Mtb, and a secA2 deletion mutant was attenuated in mice (Braunstein et al 2003) and has a proapoptosis phenotype because of its defect in SodA secretion (Hinchey et al 2007).…”

Virulence Factors and Pathogenicity of Mycobacterium

“…Pathogenic mycobacterium species express and secrete higher levels of SodA compared to the non-pathogenic species. In fact, MTB mutants with reduced SodA expression displayed increased susceptibility to H 2 O 2 and were markedly attenuated in mice [102]. Although SodA lacks a classical signal sequence for protein export, it is a protein dependent on SecA2…”

Thiol-Dependent Peroxidases in Mycobacterium tuberculosis Antioxidant Defense

“…Its synthesis is increased in M. smegmatis mutants in MSH synthesis suggesting a compensation mechanism (Ta et al, 2011), although the actual function of this unusual thiol remains to be investigated (Seebeck, 2010). Related to enzymatic mechanisms of reactive oxygen species detoxification, M. tuberculosis expresses a Fe-dependent superoxide dismutase, SODA (Rv3846), which is released to the extracellular medium and is considered to be important for pathogenesis (Edwards et al, 2001); it also express a Cu-dependent SODC (Rv0432) that is not essential for intracellular growth within macrophages and seems to play a minor role in pathogenicity (Dussurget et al, 2001). M. tuberculosis contains different thioredoxin-related enzymes which are maintained at reduced state by thioredoxin reductase and NADPH (Jaeger et al, 2004).…”