However, it

is unclear whether the only reason of attenua

However, it

is unclear whether the only reason of attenuation of cholesterol degradation mutants in MØ is due to their inability to use cholesterol as a source of carbon and energy. It was previously found that a mutant lacking an intact hsaC gene accumulated catechol derivatives that appeared to be toxic to Mtb [12]. The attenuated growth of the ∆kstD mutant in resting MØ, used in the current study, was not due to the accumulation of toxic compounds, suggesting that cholesterol degradation ability per se is essential for the replication of tubercle bacilli inside MØ [10]. On the other hand, the lack of a functional copy of kstD might modify the basic metabolism affecting pathogenic features of the bacilli. The mutant ΔkshB revealed unusual change in the structure of the cell wall which was thickened PND-1186 supplier and loosened as KPT-8602 in vitro a result of the synthesis of lipid types other than those in wild-type Mtb [11]. Such modification of the cell envelope can influence the pathogenicity of Mtb. It was also suggested that cholesterol metabolism of Mtb may contribute to the production of specific virulence factors and/or disruption of host

cell signaling [24]. Moreover, the in vivo cholesterol degradation by Mtb can affect the activity of MØ. In our studies the ∆kstD failed to inhibit ROS and NO production in resting MØ compared to wild-type and complemented strains. It is generally accepted that ROS and RNIs kill or inhibit intracellular growth of Mtb [8, 25, 26]. Similar to previous report [27], we found that Mtb induced ROS production in MØ immediately after phagocytosis (data not shown). The increased oxidative response in MØ infected with ∆kstD unable to metabolize cholesterol can be directly related to cholesterol degradation process (e.g. if cholesterol Calpain metabolite HKI-272 order modifies the signaling of enzymes involved in NO and ROS production) or can be a derivative of attenuation of bacilli inside MØ. To clarify this issue we used two different Mtb mutants, not related to cholesterol

degradation process and showing attenuated growth in THP-1, to test them in respect to inhibition of ROS/NO production in macrophages (data not shown). Only one of them was able to inhibit ROS/NO production to the level of the wild type strain. Therefore the most likely interpretation of our result is that ROS/NO over-production in resting MØ infected with ΔkstD results from the attenuation of the mutant’s growth inside MØ, however the specific role of cholesterol degradation intermediates cannot be excluded. Changes in the cholesterol level in plasma membrane modulate the activity of the proteins and the receptors located in the lipid rafts. The components of NADPH oxidase are known to migrate to the plasma membrane of newly formed phagosome. The recruitment of NADPH oxidase subunits and their assembly in the membrane are necessary for an oxidative burst execution [28].

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1. 2-fold respectively, as compared to the wild type [27] Table 2 C
2. The triple mutant PS111 grew very poorly and was hypersusceptible
3. The triple mutant PS111 grew very poorly and was hypersusceptible
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