Integration of computational modelling with transcription and gene essentiality profiling of both MTB bacillus and infected human dendritic cells and macrophages to understand molecular interaction networks involved in the host pathogen cross-talk – ERASYSBIO (ANR-09-SYSB-0005)

Mycobacterium tuberculosis is a major pathogen of man. Drug treatment is available for human disease but it takes six months, which is impractical in developing world settings where TB is most common. Consequent non-compliance with treatment regimes leads to the emergence of drug resistance. This is now a major world-wide problem with practically incurable “extreme drug-resistant” strains appearing in many countries. In this project we will study the molecular mechanisms of the interaction between Mycobacterium tuberculosis and human immune system. The knowledge about these mechanisms is necessary for the development of new therapeutic approaches and vaccines which are needed to shorten TB treatment and combat drug resistant strains. We will focus on the interaction of the pathogen with dendritic cells and macrophages, which are cell types active during the immune system response to the infection. The M. tuberculosis is capable of infecting macrophages, but not dendritic cells. Therefore, comparison of the responses of these two cell types to M. tuberculosis will highlight the mechanisms participating in host pathogen interaction. To understand the complex phenomenon of host-pathogen interaction the Systems Biology approach has to be employed, where molecular biology methods are integrated with computational modelling approaches to study cells at the whole genome scale level. We will use state of the art functional genomics techniques to compare interaction of the pathogen with dendritic cells and macrophages and identify human and bacterial genes, which are involved in host-pathogen interaction. The voluminous experimental data sets will be analyzed in the context of the literature knowledge about the vast networks of interacting molecules in the living cells. The computer simulation approaches developed in the physical sciences and engineering fields will be used. The computer models will generate hypotheses, which will be subjected to experimental verification. At the end of the project we expect to deliver a set of models of the molecular interaction networks involved in the interaction of M. tuberculosis with immune system. These models can be used to design therapeutic, diagnostic and vaccination strategies