Abstract
BackgroundMycobacterium tuberculosis infection in humans is often associated with extended period of latency. To adapt to the hostile hypoxic environment inside a macrophage, M. tuberculosis cells undergo several physiological and metabolic changes. Previous studies have mostly focused on inspecting individual facets of this complex process. In order to gain deeper insights into the infection process and to understand the coordination among different regulatory/ metabolic pathways in the pathogen, the current in silico study investigates three aspects, namely, (i) host-pathogen interactions (HPIs) between human and M. tuberculosis proteins, (ii) gene regulatory network pertaining to adaptation of M. tuberculosis to hypoxia and (iii) alterations in M. tuberculosis metabolism under hypoxic condition. Subsequently, cross-talks between these components have been probed to evaluate possible gene-regulatory events as well as HPIs which are likely to drive metabolic changes during pathogen’s adaptation to the intra-host hypoxic environment.ResultsThe newly identified HPIs suggest the pathogen’s ability to subvert host mediated reactive oxygen intermediates/ reactive nitrogen intermediates (ROI/ RNI) stress as well as their potential role in modulating host cell cycle and cytoskeleton structure. The results also indicate a significantly pronounced effect of HPIs on hypoxic metabolism of M. tuberculosis. Findings from the current study underscore the necessity of investigating the infection process from a systems-level perspective incorporating different facets of intra-cellular survival of the pathogen.ConclusionsThe comprehensive host-pathogen interaction network, a Boolean model of M. tuberculosis H37Rv (Mtb) hypoxic gene-regulation, as well as a genome scale metabolic model of Mtb, built for this study are expected to be useful resources for future studies on tuberculosis infection.
Highlights
Mycobacterium tuberculosis infection in humans is often associated with extended period of latency
Host-pathogen interactions (HPI) between human and M. tuberculosis H37Rv (Mtb) A template protein-protein interaction (PPI) library was constructed by collating PPI related information from different public resources and potential HPIs between human and Mtb proteins was obtained by interlogs mapping approach
The final set of HPIs comprised of 178 intra-species PPIs involving 148 human and 30 Mtb proteins (Fig. 1)
Summary
Mycobacterium tuberculosis infection in humans is often associated with extended period of latency. In order to gain deeper insights into the infection process and to understand the coordination among different regulatory/ metabolic pathways in the pathogen, the current in silico study investigates three aspects, namely, (i) host-pathogen interactions (HPIs) between human and M. tuberculosis proteins, (ii) gene regulatory network pertaining to adaptation of M. tuberculosis to hypoxia and (iii) alterations in M. tuberculosis metabolism under hypoxic condition. Cross-talks between these components have been probed to evaluate possible gene-regulatory events as well as HPIs which are likely to drive metabolic changes during pathogen’s adaptation to the intra-host hypoxic environment. Mycobacterial proteins involved in host-pathogen interactions are likely to play crucial roles in sensing the host environment and subsequently participate (directly or indirectly) in regulatory events, leading to physiological/ metabolic changes necessary for intra-cellular survival. Understanding of the M. tuberculosis survival strategies, including changes in gene regulatory cascades as well as metabolism, would remain incomplete unless studied in context of the host-pathogen interactions
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