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The role of 3-ketosteroid 1(2)-dehydrogenase in the pathogenicity of... » Isaúde
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BMC microbiology [electronic resource]
2013-02-21 03:07:36

The role of 3-ketosteroid 1(2)-dehydrogenase in the pathogenicity of Mycobacterium tuberculosis

Descrição: Background:A growing body of evidence suggests that Mycobacterium tuberculosis (Mtb) uses the host\'s cholesterol as a source of carbon and energy during infection. Strains defective in cholesterol transport or degradation exhibit attenuated growth in activated macrophages and diminished infectivity in animal models. The aim of this study was to evaluate intracellular replication of a cholesterol degradation-deficient Mtb mutant in human macrophages (M[latin capital letter o with stroke]) in vitro and assess the functional responses of Mtb mutant-infected M[latin capital letter o with stroke].Results:A mutant Mtb H37Rv strain containing an inactivated kstD gene ([increment]kstD), which encodes 3-ketosteroid 1(2)-dehydrogenase (KstD), was previously prepared using the homologous recombination-based gene-replacement technique. A control strain carrying the kstD gene complemented with an intact kstD was also previously constructed. In this study, human resting M[latin capital letter o with stroke] were obtained after overnight differentiation of the human monocyte-macrophage cell line THP-1. Resting M[latin capital letter o with stroke] were further activated with interferon-gamma (IFN-gamma). The ability of the kstD-defective Mtb mutant strain to replicate intracellularly in human M[latin capital letter o with stroke] was evaluated using a colony-forming assay. Nitric oxide (NO) and reactive oxygen species (ROS) production by M[latin capital letter o with stroke] infected with wild-type or [increment]kstD strains was detected using Griess reagent and chemiluminescence methods, respectively. The production of tumor necrosis factor-alpha and interleukin-10 by M[latin capital letter o with stroke] after infection with wild-type or mutant Mtb was examined using enzyme-linked immunosorbent assays.We found that replication of mutant Mtb was attenuated in resting M[latin capital letter o with stroke] compared to the wild-type or complemented strains. Moreover, the mutant was unable to inhibit the NO and ROS production induced through Toll-like receptor 2 (TLR2) signaling in infected resting M[latin capital letter o with stroke]. In contrast, mutant and wild-type Mtb behaved similarly in M[latin capital letter o with stroke] activated with IFN-gamma before and during infection.Conclusions:The Mtb mutant DeltakstD strain, which is unable to use cholesterol as a source of carbon and energy, has a limited ability to multiply in resting M[latin capital letter o with stroke] following infection, reflecting a failure of the DeltakstD strain to inhibit the TLR2-dependent bactericidal activity of resting M[latin capital letter o with stroke].

Identificador: doi:10.1186/1471-2180-13-43
Volume: 0
Página: 4 a


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