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Molecular signatures and their interactions behind the successful establishment of infection of  Mycobacterium tuberculosis  ( Mtb ) inside macrophage are largely unknown. In this work, we present an inter-system scale atlas of the gene expression signatures, their interactions and higher order gene functions of macrophage- Mtb  environment at the time of infection. We have carried out large-scale meta-analysis of previously published gene expression microarray studies andhave identified a ranked list of differentially expressed genes and their higher order functions in intracellular  Mtb  as well as the infected macrophage. Comparative analysis of gene expression signatures of intracellular  Mtb  with the  in vitro  dormant  Mtb  at different hypoxic and oxidative stress conditions led to the identification of the large number of  Mtb  functional groups, namely operons, regulons and pathways that were common and unique to the intracellular environment and dormancy state. Some of the functions that are specific to intracellular  Mtb  are cholesterol degradation and biosynthesis of immunomodulatory phenolic compounds. The molecular signatures we have identified to be involved in adaptation to different stress conditions in macrophage environment may be critical for designing therapeutic interventions against tuberculosis. And, our approach may be broadly applicable for investigating other host-pathogen interactions.

System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection