Collectively, all evidence indicates that MglA plays a critical role for the normal oxidative stress response and that its absence renders F. tularensis severely impaired to handle reactive oxygen species. We suggest that the lower levels of reactive oxygen species generated under growth in microaerobic conditions mitigated the defect of the mutant and, consequently, it grew as well as LVS under these conditions. Our demonstration of an important role of MglA for the regulation of the fsl operon and catalase are in agreement
with two previous publications [8, 10], but if MglA directly regulates these genes is not known. selleck kinase inhibitor Our present results suggest that the aberrant expression of catalase is an indirect effect of the increased
oxidative stress of the ΔmglA mutant since the catalase activity was normalized under Stattic in vivo the microaerobic conditions. Similarly, the mutant normalized expression of fslA-D and feoB under the microaerobic conditions and this also occurred under severe iron deficiency. In contrast, iglC, known to be transcriptionally regulated by MglA, was repressed in ΔmglA regardless of growth conditions or iron availability. Together these data imply that there are also MglA-independent mechanisms that transcriptionally regulate the fsl, feoB and katG genes in F. tularensis. The increased catalase activity in the ΔmglA mutant is a likely explanation for the high resistance of the mutant to H2O2. Such a correlation was also reported for F. novicida . Besides catalase, the size of the intracellular iron pool is a factor that determines
the TPCA-1 solubility dmso susceptibility of F. tularensis to H2O2 . We recently showed that subspecies holarctica strains, including LVS, PRKACG contain more iron and were more susceptible to H2O2 than strains of subspecies tularensis . When the iron pool of the subspecies holarctica strains was depleted, their susceptibility to H2O2 decreased. Here we observed that LVS sequestered significantly more iron under the microaerobic conditions. Since iron is a factor that determines the susceptibility of F. tularensis to H2O2, it is very likely that the substantial iron pool of LVS under the microaerobic conditions contributed to its extreme susceptibility to H2O2. Iron could, however, not explain the high susceptibility of ΔmglA to H2O2 in the microaerobic milieu, but in this case the decreased activity of catalase is a probable explanation for its reduced ability to handle the toxic effects. This agrees with our previous findings that catalase plays a very important role for LVS in protection against H2O2 . The present study confirms previous findings that MglA plays an important role for the adaptation to oxidative stress in F. tularensis LVS and, moreover, we demonstrate that the role of MglA is most critical during growth in an aerobic milieu, whereas its importance is less obvious in an oxygen-restricted milieu.