About SysteMTb

Tuberculosis (Tb) is a re-emerging global health threat caused by Mycobacterium Tuberculosis (MTb). One third of the world’s population is infected with MTb; and new infections occur at a rate of one per second. Despite global research efforts, mechanisms underlying pathogenesis, virulence and persistence of MTb infection remain poorly understood.
MTb infection is best described as an equilibrium involving a balance of activation and suppression of host responses, orchestrated by a complex and dynamic series of interactions between multiple host and bacterial components. Simple reductionist approaches are insufficient to understand this complex biology. The core strategy underlying the SysteMTb project is that a systems biology approach intertwining experimentally-driven model development and model-driven experimentation will provide improvement in understanding this threatening bacterium and will be pivotal in designing rational strategies for preventive and therapeutic interventions. This entails the progressive elucidation and thorough analysis of the structural scaffolds and cellular wiring of MTb through the measurement of its global responses (metabolomics, lipidomics, proteomics, transcriptomics, glycomics) upon perturbations (chemical challenges, knock-out/knock-down mutants, etc.) which are relevant for infection, more specifically macrophage infection.

Fig.1 Organisation of the work within the SysteMTb

Fig. 1 Organization of the work within SysteMTb

The grand goal of the SysteMTb project is to establish a Systems Biology framework to understand key features of MTb and its interactions with the host which in turn will provide new insights and a solid (model based) knowledge for the development of novel and cost-effective strategies to combat tuberculosis. The workflow will be structured along three main objectives in four sub-projects (SP).

Overall SysteMTb will produce for the first time an almost complete Systems Biology analysis of a microorganism under the same set of standard conditions.

Sub-projects

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Sub-project 1 - Protein function and complexes

The sub-project consists of four work packages (WPs) and its main goal is to characterize protein complexes within Mtb and between Mtb and the host macrophages, in terms of physical interactions, structure, function and localization. The WPs are dedicated to analyze
- protein complexes by affinity purification and mass spectrometry (WP2)
- protein function and structure by biochemical assays and X-ray crystallography (WP3)
- protein localizations by light microscopy (WP4).
A cloning facility (WP1) will provide all the necessary vectors to the other WPs and create a central vector collection, available to the scientific community.

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Sub-project 2 - Omics

The sub-project aims at generating a comprehensive set of omics data for the Mtb strains H37Rv and BCG during logarithmic and stationary phases of growth under a variety of environmental conditions reflecting those in macrophages. It will collect data on
- transcriptomics (including coding and non-coding transcripts) (WP6)
- metabolome (WP7)
- proteome and phosphoproteome (WP8)
- lipidome and glycome (WP9)
A key aspect of the organisation of SP2 will be to ensure that data are generated using identical lots under carefully standardised growth conditions. This will be achieved by coordination through WP5.

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Sub-project 3 - Bioinformatics

The “Bioinformatics” sub-project is very central in the project, “gluing” the different WPs together. It will
-  provide a data storage, exchange platform and perform data integration of the data collected in sub-projects 1 and 2 (WP10) and redistribute data in a standardized format to the modelling groups
- generate tools (WP11) to visualize „omics‟ data in the context of the metabolism and the protein-interaction network
- update genome annotation with predictions from genome-context methods, presence/absence patterns in Mtb strains and new interactions (WP12).
This sub-project will feed sub-project 4 with processed data in a format amenable for simulations.

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Sub-project 4 - Modelling

The sub-project will provide a modelling scaffold to study Mtb internal wiring and dynamic interplay within a host environment. To this end, it is proposed to
- develop a mathematical framework that accounts for the major features of the host-pathogen interactions including its global metabolic and transport network, global stress responses (including interactions with host cells), (non-)transcriptional regulation networks and cell-division derived properties
- then to use this framework in order to
a) explore the propagation of disturbances throughout essential signalling systems, cell cycle, metabolic and regulatory networks
b) identify critical (sensitive) nodes and threshold values leading to different responses
c) generate new hypotheses that will be explored in the experimental WP16