Abstract
The success of Mycobacterium tuberculosis as a pathogen derives from its facile adaptation to the intracellular milieu of human macrophages. To explore this process, we asked whether adaptation also required interference with the metabolic machinery of the host cell. Temporal profiling of the metabolic flux, in cells infected with differently virulent mycobacterial strains, confirmed that this was indeed the case. Subsequent analysis identified the core subset of host reactions that were targeted. It also elucidated that the goal of regulation was to integrate pathways facilitating macrophage survival, with those promoting mycobacterial sustenance. Intriguingly, this synthesis then provided an axis where both host- and pathogen-derived factors converged to define determinants of pathogenicity. Consequently, whereas the requirement for macrophage survival sensitized TB susceptibility to the glycemic status of the individual, mediation by pathogen ensured that the virulence properties of the infecting strain also contributed towards the resulting pathology.
Highlights
Pathogenicity of Mycobacterium tuberculosis (Mtb) has been attributed to the plasticity of its central carbon metabolism (CCM) machinery, which facilitates ready adaptation of pathogen to the intracellular milieu of the macrophage [1]
To investigate how Mtb infection influences CCM of the host macrophage we examined time-dependent modulations in macrophage metabolism, after infection with mycobacterial strains that varied in both genotype and phenotype
Mtb infects macrophages and it adapts to the hostile intracellular milieu of this cell by exploiting the plasticity of its central carbon metabolism machinery
Summary
Pathogenicity of Mycobacterium tuberculosis (Mtb) has been attributed to the plasticity of its central carbon metabolism (CCM) machinery, which facilitates ready adaptation of pathogen to the intracellular milieu of the macrophage [1]. While Mtb adaption to host requires the switch in bacterial CCM towards catabolism of host lipid substrates [2,3,4,5], optimal exploitation of this switch involves pathogen-induced promotion of lipid body (LB) accumulation by the host macrophage [6,7,8]. We discovered that expression of virulence required the pathogen to engage with a unique subset of host metabolic pathways Characterization of these pathways revealed that metabolic thresholds governing host cell survival were tightly assimilated with mechanisms regulating intracellular survival of the bacilli. This synthesis provided the framework for convergence of both host- and pathogen-derived factors, in dictating the pathology of Mtb infection
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