Role of KatG catalase‐peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst

Abstract

SummaryReactive nitrogen species (RNS) play an essential role in host defence against Mycobacterium tuberculosis (MTB) in the mouse model of tuberculosis (TB), as evidenced by the increased susceptibility of mice deficient in the inducible isoform of nitric oxide synthase (NOS2). In contrast, the role of reactive oxygen species (ROS) in protection against MTB is less clear, and mice defective in the ROS-generating phagocyte NADPH oxidase (Phox) are relatively resistant. This suggests that MTB might possess efficient mechanisms to evade or counter the phagocyte oxidative burst, effectively masking the impact of this host defence mechanism. In order to assess the role of ROS detoxification pathways in MTB virulence, we generated a katG null mutant of MTB, deficient in the KatG catalase-peroxidase-peroxynitritase, and evaluated the mutant's ability to replicate and persist in macrophages and mice. Although markedly attenuated in wild-type C57Bl/6 mice and NOS2 -/-mice, the D D D D katG MTB strain was indistinguishable from wildtype MTB in its ability to replicate and persist in gp91 Phox-/-mice lacking the gp91 subunit of NADPH oxidase. Similar observations were made with murine bone marrow macrophages infected ex vivo : growth of the D D D D katG MTB strain was impaired in macrophages from C57Bl/6 and NOS2 -/-mice, but indistinguishable from wild-type MTB in gp91 Phox-/-macrophages. These results indicate that the major role of KatG in MTB pathogenesis is to catabolize the peroxides generated by the phagocyte NADPH oxidase; in the absence of this host antimicrobial mechanism, KatG is apparently dispensable.

S-nitroso proteome ofMycobacterium tuberculosis: Enzymes of intermediary metabolism and antioxidant defense

“…Also identified was catalase (KatG), an enzyme crucial to Mtb's defense against reactive oxygen intermediates as revealed when NOS2 is absent (27). Thus, in addition to enzymes of intermediary and lipid metabolism, the Mtb S-nitroso proteome includes enzymes that participate in Mtb's defenses against oxidative or nitrosative injury.…”

“…Transcriptional adaptation of Mtb within the phagosome of the activated macrophage depends on macrophage expression of NOS2, and a large component of that response can be mimicked by exposing cultures of Mtb to mildly acidified nitrite (26). In contrast, the phagocyte oxidase is not required for mice to control Mtb infection (25), in part because of the protection afforded by Mtb's katG-encoded KatG peroxidase (27). Finally, the brief activity of phagocyte oxidase after uptake of Mtb (28) precedes the induction of NOS2, limiting the amount of peroxynitrite that might arise in the phagosome from the mutual reaction of O 2 Ϫ and NO, the short-lived products of those two enzymes.…”

Evidence for Mycobacteria in Sarcoidosis

“…Most of these sequences were identified as MTB SodA, but two were non-MTB (80). Using a distinct approach and in situ hybridization, Song and coworkers found evidence of mycobacterial catalase-peroxidase antigen (mKatG), another mycobacterial virulence factor, and MTB 16S rRNA DNA in a similar proportion of sarcoidosis tissues (z 40%) (81,82). Of note, 83% of the tissues that reacted with the mKatG probe were positive for MTB 16S rRNA, but none of the control samples was positive for either probe.…”

Virulence Factors and Pathogenicity of Mycobacterium

“…Thus the major role of KatG in TB pathogenesis is to catabolize the peroxides generated by the phagocyte NADPH oxidase; although in the absence of this host antimicrobial mechanism, KatG is apparently dispensable [105]. Moreover, KatG also activates the anti-tuberculosis drug isoniazid (INH) converting it to several reactive species that inhibits a mycolic acid biosynthesis [105]. Although isoniazid resistance is multigenic, mutations in katG predominate among the INH-resistant strains, but the effect of these mutations on MTB virulence is variable.…”

“…Although isoniazid resistance is multigenic, mutations in katG predominate among the INH-resistant strains, but the effect of these mutations on MTB virulence is variable. In general, katG mutations render MTB strains sensitive to endogenous or exogenous peroxides, generated during bacteria respiration or by phagocytes during infection [105], maybe because mutations also affect the peroxidase domain of KatG [106] though the activity of the alkyl hydroperoxidase C (AhpC) has been described as an important compensatory mechanism in INH-resistant strains [107].…”